Spirocyclic compounds as agonists of the muscarinic m1 receptor and/or m4 receptor

ABSTRACT

This invention relates to compounds that are agonists of the muscarinic M1 and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula. (I) where p, q, r, s, X, Z, Y, R 1 , R 2 , R 3  and R 4  are as defined herein.

This invention relates to a class of novel spirocyclic compounds, their salts, pharmaceutical compositions containing them and their use in therapy of the human body. In particular, the invention is directed to a class of compounds, which are agonists of the muscarinic M₁ receptor and/or M₄ receptor, and hence are useful in the treatment of Alzheimer's disease, schizophrenia, cognitive disorders and other diseases mediated by the muscarinic M₁/M₄ receptors, as well as the treatment or alleviation of pain.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily which mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁ mAChR is predominantly expressed post-synaptically in the cortex, hippocampus, striatum and thalamus; M₂ mAChRs are located predominantly in the brainstem and thalamus, though also in the cortex, hippocampus and striatum where they reside on cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are also expressed peripherally on cardiac tissue (where they mediate the vagal innervation of the heart) and in smooth muscle and exocrine glands. M₃ mAChRs are expressed at relatively low level in the CNS but are widely expressed in smooth muscle and glandular tissues such as sweat and salivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁ mAChR, play a critical role in mediating higher cognitive processing. Diseases associated with cognitive impairments, such as Alzheimer's disease, are accompanied by loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982 Science). In schizophrenia, which is also characterised by cognitive impairments, mAChR density is reduced in the pre-frontal cortex, hippocampus and caudate putamen of schizophrenic subjects (Dean et al., 2002 Mol Psychiatry). Furthermore, in animal models, blockade or lesion of central cholinergic pathways results in profound cognitive deficits and non-selective mAChR antagonists have been shown to induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy has largely been based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to dose-limiting side effects resulting from stimulation of peripheral M₂ and M₃ mAChRs including disturbed gastrointestinal motility, bradycardia, nausea and vomiting

(http://www.drugs.com/pro/donepezil.html; http://www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁ mAChR agonists to target increases in cognitive function. Such efforts resulted in the identification of a range of agonists, exemplified by compounds such as xanomeline, AF267B, sabcomeline, milameline and cevimeline. Many of these compounds have been shown to be highly effective in pre-clinical models of cognition in both rodents and/or non-human primates. Milameline has shown efficacy versus scopolamine-induced deficits in working and spatial memory in rodents; sabcomeline displayed efficacy in a visual object discrimination task in marmosets and xanomeline reversed mAChR antagonist-induced deficits in cognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder (26.6 million people worldwide in 2006) that affects the elderly, resulting in profound memory loss and cognitive dysfunction. The aetiology of the disease is complex, but is characterised by two hallmark brain sequelae: aggregates of amyloid plaques, largely composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau proteins. The accumulation of Aβ is thought to be the central feature in the progression of AD and, as such, many putative therapies for the treatment of AD are currently targeting inhibition of Aβ production. Aβ is derived from proteolytic cleavage of the membrane bound amyloid precursor protein (APP). APP is processed by two routes, non-amyloidgenic and amyloidgenic. Cleavage of APP by γ-secretase is common to both pathways, but in the former APP is cleaved by an α-secretase to yield soluble APPα. The cleavage site is within the Aβ sequence, thereby precluding its formation. However, in the amyloidgenic route, APP is cleaved by β-secretase to yield soluble APPβ and also Aβ. In vitro studies have shown that mAChR agonists can promote the processing of APP toward the soluble, non-amyloidogenic pathway. In vivo studies showed that the mAChR agonist, AF267B, altered disease-like pathology in the 3×TgAD transgenic mouse, a model of the different components of Alzheimer's disease (Caccamo et al., 2006 Neuron). Finally, the mAChR agonist cevimeline has been shown to give a small, but significant, reduction in cerebrospinal fluid levels of Aβ in Alzheimer's patients, thus demonstrating potential disease modifying efficacy (Nitsch et al., 2000 Neurol).

Furthermore, preclinical studies have suggested that mAChR agonists display an atypical antipsychotic-like profile in a range of pre-clinical paradigms. The mAChR agonist, xanomeline, reverses a number of dopamine driven behaviours, including amphetamine induced locomotion in rats, apomorphine induced climbing in mice, dopamine agonist driven turning in unilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest in monkeys (without EPS liability). It also has been shown to inhibit A10, but not A9, dopamine cell firing and conditioned avoidance and induces c-fos expression in prefrontal cortex and nucleus accumbens, but not in striatum in rats. These data are all suggestive of an atypical antipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev). Muscarinic receptors have also been implicated in the neurobiology of addiction. The reinforcing effects of cocaine and other addictive substances are mediated by the mesolimbic dopamine system where behavioral and neurochemical studies have shown that the cholinergic muscarinic receptor subtypes play important roles in regulation of dopaminergic neurotransmission. For example M(4) (−/−) mice demonstrated significantly enhanced reward driven behaviour as result of exposure to cocaine (Schmidt et al Psychopharmacology (2011) August; 216(3):367-78). Furthermore xanomeline has been demonstrated to block the effects of cocaine in these models.

Xanomeline, sabcomeline, milameline and cevimeline have all progressed into various stages of clinical development for the treatment of Alzheimer's disease and/or schizophrenia. Phase II clinical studies with xanomeline demonstrated its efficacy versus various cognitive symptom domains, including behavioural disturbances and hallucinations associated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol). This compound was also assessed in a small Phase II study of schizophrenics and gave a significant reduction in positive and negative symptoms when compared to placebo control (Shekhar et al., 2008 Am J Psych). However, in all clinical studies xanomeline and other related mAChR agonists have displayed an unacceptable safety margin with respect to cholinergic side effects, including nausea, gastrointestinal pain, diarrhea, diaphoresis (excessive sweating), hypersalivation (excessive salivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Pain can be divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage however management of post-surgical pain is required. Inflammatory pain may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion and is triggered by the action of inflammatory mediators such as neuropeptides and prostaglandins which result in neuronal inflammation and pain. Neuropathic pain is associated with abnormal painful sensations to non-painful stimuli. Neuropathic pain is associated with a number of different diseases/traumas such as spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), viral infection (such as HIV or Herpes). It is also common in cancer both as a result of the disease or a side effect of chemotherapy. Activation of muscarinic receptors has been shown to be analgesic across a number of pain states through the activation of receptors in the spinal cord and higher pain centres in the brain. Increasing endogenous levels of acetylcholine through acetylcholinesterase inhibitors, direct activation of muscarinic receptors with agonists or allosteric modulators has been shown to have analgesic activity. In contrast blockade of muscarinic receptors with antagonists or using knockout mice increases pain sensitivity. Evidence for the role of the M₁ receptor in pain is reviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified which display improved selectivity for the M₁ mAChR subtype over the peripherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg Med Chem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al., 2010 ACS Med Chem Lett). Despite increased levels of selectivity versus the M₃ mAChR subtype, some of these compounds retain significant agonist activity at both this subtype and the M₂ mAChR subtype. Herein we describe a series of compounds which unexpectedly display high levels of selectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptor subtypes.

THE INVENTION

The present invention provides compounds having activity as muscarinic M₁ and/or M₄ receptor agonists. More particularly, the invention provides compounds that exhibit selectivity for the M₁ or M₄ receptor relative to the M₂ and M₃ receptor subtypes. Accordingly, in a first embodiment (Embodiment 1.1), the invention provides a compound of the formula (1):

or a salt thereof, wherein: p is 0 or 1; q is 1 or 2; r is 1 or 2; s is 1 or 2, where the total of r and s is 2 or 3;

X is C or N; Z is CH₂, N, O or S; Y is N, O, S or CH₂;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; or R¹ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R³ can be independently H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl.

Particular and preferred compounds of the formula (1) are as defined in the following Embodiments 1.2 to 1.67:

1.2 A compound according to Embodiment 1.1 wherein R¹ is H or a C₁₋₆ non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbon multiple bonds, wherein the hydrocarbon group is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof. 1.3 A compound according to either of Embodiments 1.1 and 1.2 wherein R¹ is selected from H; C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl; and C₁₋₆ non-aromatic hydrocarbon groups consisting of or containing a C₃₋₆ cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon groups being optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon groups may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof. 1.4 A compound according to Embodiment 1.1 wherein R¹ is a group W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, or R¹ and R₂ are joined together to form a ring, which may be fused or spirocyclic. 1.5 A compound according to Embodiment 1.1 wherein R¹ is NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵ where R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.6 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹ is selected from:

-   -   H;     -   Halogen;     -   Cyano;     -   OH;     -   C₁₋₃ alkoxy;     -   NH₂;     -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;     -   C₂₋₆ alkenyl;     -   C₂₋₆ alkynyl;     -   C₃₋₆ cycloalkyl;     -   C₅₋₆ cycloalkenyl;     -   aryl;     -   heteroaryl;     -   CH₂-aryl;     -   CH₂-heteroaryl;     -   NR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆alkyl;     -   COOR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   CONR⁵R⁶ where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;     -   NR⁷CONR⁵R⁶, where R⁵, R⁶ and R⁷ are independently H, C₁₋₆ alkyl;     -   NR⁷COOR⁵, where R⁵ and R⁷ are independently H, C₁₋₆ alkyl;     -   OCONR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;     -   SR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SOR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SO₂R⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SO₃R⁵, where R⁵ is H, C₁₋₆ alkyl;     -   a spirocycle of formula (CH₂)n where n is 2, 3, 4, 5 or 6.         1.7 A compound according to Embodiment 1.6 wherein R¹ is H or         C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms.         1.8 A compound according to Embodiment 1.6 wherein R¹ is H or         C₁₋₅ alkyl.         1.9 A compound according to any one of Embodiments 1.1 to 1.8         wherein R² is H or a C₁₋₆ non-aromatic hydrocarbon group         containing 0, 1 or 2 carbon-carbon multiple bonds, wherein the         hydrocarbon group is optionally substituted with one to six         fluorine atoms and wherein one or two, but not all, carbon atoms         of the hydrocarbon group may optionally be replaced by a         heteroatom selected from O, N and S and oxidised forms thereof.         1.10 A compound according to any one of Embodiments 1.1 to 1.9         wherein R² is selected from H; C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆         alkynyl; and C₁₋₆ non-aromatic hydrocarbon groups consisting of         or containing a C₃₋₆ cycloalkyl or C₅₋₆ cycloalkenyl group; each         of the said alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon         groups being optionally substituted with one to six fluorine         atoms and wherein one or two, but not all, carbon atoms of each         of the alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon         groups may optionally be replaced by a heteroatom selected from         O, N and S and oxidised forms thereof.         1.11 A compound according to any one of Embodiments 1.1 to 1.8         wherein R² is a group W or CH₂—W where W is an optionally         substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl         or heteroaryl ring, or R¹ and R² are joined together to form a         ring, which may be fused or spirocyclic.         1.12 A compound according to any one of Embodiments 1.1 to 1.8         wherein R² is NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵,         OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵ where R⁵, R⁶ and R⁷ can be         independently H, C₁₋₆ alkyl.         1.13 A compound according to any one of Embodiments 1.1 to 1.12         wherein R² is selected from:     -   H;     -   Halogen;     -   Cyano;     -   OH;     -   C₁₋₃ alkoxy;     -   NH₂;     -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;     -   C₂₋₆ alkenyl;     -   C₂₋₆ alkynyl;     -   C₃₋₆ cycloalkyl;     -   C₅₋₆ cycloalkenyl;     -   aryl;     -   heteroaryl;     -   CH₂-aryl;     -   CH₂-heteroaryl;     -   NR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆alkyl;     -   COOR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   CONR⁵R⁶ where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;     -   NR⁷CONR⁵R⁶, where R⁵, R⁶ and R⁷ are independently H, C₁₋₆ alkyl;     -   NR⁷COOR⁵, where R⁵ and R⁷ are independently H, C₁₋₆ alkyl;     -   OCONR⁵R⁶, where R⁵ and R⁶ are independently H, C₁₋₆ alkyl;     -   SR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SOR⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SO₂R⁵, where R⁵ is H, C₁₋₆ alkyl;     -   SO₃R⁵, where R⁵ is H, C₁₋₆ alkyl.         1.13a A compound according to Embodiment 1.13 wherein R² is H or         C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms.         1.14 A compound according to Embodiment 1.13 wherein R² is H or         C₁₋₆ alkyl.         1.15 A compound according to any one of Embodiments 1.1 to 1.14         wherein R¹ and R² are selected from hydrogen and C₁₋₆ alkyl.         1.16 A compound according to Embodiments 1.15 wherein R¹ and R²         are independently H, methyl, ethyl, propyl, isopropyl or benzyl.         1.17 A compound according to Embodiment 1.1 wherein R¹ and R²         together or the R³ and R² together form an optionally         substituted cycloalkyl or heterocycloalkyl ring. The ring can         replace the R³ group on the nitrogen. The ring may be fused or         spirocyclic.         1.18 A compound according to Embodiment 1.17 wherein R¹ and R²         together form a cycloalkyl ring optionally incorporating a         maximum of 2 heteroatoms selected from O, S or N, and optionally         substituted by a maximum of 6 atoms of F.         1.19 A compound according to Embodiment 1.1 wherein R³ is H or a         C₁₋₆ non-aromatic hydrocarbon group containing 0, 1 or 2         carbon-carbon multiple bonds, wherein the hydrocarbon group is         optionally substituted with one to six fluorine atoms and         wherein one or two, but not all, carbon atoms of the hydrocarbon         group may optionally be replaced by a heteroatom selected from         O, N and S and oxidised forms thereof.         1.20 A compound according to either of Embodiment 1.19 wherein         R³ is selected from H; C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl;         and C₁₋₆ non-aromatic hydrocarbon groups consisting of or         containing a C₃₋₆ cycloalkyl or C₅₋₆ cycloalkenyl group; each of         the said alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon         groups being optionally substituted with one to six fluorine         atoms and wherein one or two, but not all, carbon atoms of each         of the alkyl, alkenyl, alkynyl and non-aromatic hydrocarbon         groups may optionally be replaced by a heteroatom selected from         O, N and S and oxidised forms thereof.         1.21 A compound according to Embodiment 1.19 wherein R³ is a         group W or CH₂—W where W is an optionally substituted 5 or 6         membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring,         or R¹ and R₂ are joined together to form a ring, which may be         fused or spirocyclic.         1.22 A compound according to any one of Embodiments 1.19 to 1.21         wherein R³ is selected from:     -   H;     -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;     -   C₂₋₆ alkenyl;     -   C₂₋₆ alkynyl;     -   C₃₋₆ cycloalkyl;     -   C₅₋₆ cycloalkenyl;     -   aryl;     -   heteroaryl;     -   CH₂-aryl;     -   CH₂-heteroaryl.         1.23 A compound according to Embodiment 1.22 wherein R³ is H or         C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms.         1.24 A compound according to Embodiment 1.5 wherein R³ is H or         C₁₋₅ alkyl.         1.25 A compound according to any one of Embodiments 1.1 to 1.24         wherein Z is CH₂, N, O or S.         1.26 A compound according to Embodiment 1.25 wherein Z is CH₂ N         or O.         1.27 A compound according to Embodiment 1.25 wherein Z is CH₂.         1.28 A compound according to Embodiment 1.25 wherein Z is N.         1.29 A compound according to Embodiment 1.25 wherein Z is O.         1.30 A compound according to any one of Embodiments 1.1 to 1.29         wherein R⁴ is H or an acyclic C₁₋₄ hydrocarbon group optionally         substituted with one or more fluorine atoms.         1.31 A compound according to Embodiment 1.30 wherein R⁴ is H or         an acyclic C₁₋₃ hydrocarbon group optionally substituted with         one or more fluorine atoms.         1.32 A compound according to Embodiment 1.31 wherein R⁴ is H or         a C₁₋₃ alkyl group or a C₁₋₂ alkynyl group.         1.33 A compound according to Embodiment 1.32 wherein R⁴ is         selected from H, methyl, fluoromethyl, ethyl, ethynyl and         1-propynyl.         1.34 A compound according to Embodiment 1.33 wherein R⁴ is         methyl.         1.35 A compound according to any one of Embodiments 1.1 to 1.34         wherein p is 0 or 1.         1.36 A compound according to Embodiment 1.35 wherein p is 0.         1.37 A compound according to Embodiment 1.35 wherein p is 1.         1.38 A compound according to any one of Embodiments 1.1 to 1.37         wherein Y is N, O or CH₂.         1.39 A compound according to Embodiment 1.38 wherein Y is N.         1.40 A compound according to Embodiment 1.38 wherein Y is O.         1.41 A compound according to Embodiment 1.38 wherein Y is S.         1.42 A compound according to any one of Embodiments 1.1 to 1.41         wherein R⁵ is H or C₁₋₆ alkyl.         1.43 A compound according to Embodiment 1.42 wherein R⁵ is H.         1.44 A compound according to Embodiment 1.42 wherein R⁵ is C₁₋₃         alkyl.         1.45 A compound according to any one of Embodiments 1.1 to 1.44         wherein R⁶ is H or C₁₋₅ alkyl.         1.46 A compound according to Embodiment 1.45 wherein R⁶ is H.         1.47 A compound according to Embodiment 1.45 wherein R⁶ is C₁₋₃         alkyl.         1.48 A compound according to any one of Embodiments 1.1 to 1.47         wherein R⁷ is H or C₁₋₅ alkyl.         1.49 A compound according to Embodiment 1.48 wherein R⁷ is H.         1.50 A compound according to Embodiment 1.48 wherein R⁷ is C₁₋₃         alkyl.         1.51 A compound according to any one of Embodiments 1.1 to 1.50         wherein X is C.         1.52 A compound according to any one of Embodiments 1.1 to 1.51         wherein r is 1.         1.53 A compound according to any one of Embodiments 1.1 to 1.51         wherein r is 2.         1.54 A compound according to Embodiment 1.1 having the formula         (2):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, O or S; Y is N, O, S or CH₂;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R³ can be independently H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.55 A compound according to Embodiment 1.1 having the formula (3):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, or O;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅ alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.56 A compound according to Embodiments 1.54 or 1.55 wherein p, q, X, Z, Y, R¹, R², R³ and R⁴ are as defined in any one of Embodiments 1.1 to 1.53.1.57 A compound according to Embodiment 1.1 having the formula (4):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, O or S; Y is N, O, S or CH₂;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R³ can be independently H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.58 A compound according to Embodiment 1.1 having the formula (5):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, or O;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.59 A compound according to Embodiments 1.54 or 1.55 wherein p, q, X, Z, Y, R¹, R², R³ and R⁴ are as defined in any one of Embodiments 1.1 to 1.53. 1.60 A compound according to Embodiment 1.1 having the formula (6):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, O or S; Y is N, O, S or CH₂;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R³ can be independently H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.61 A compound according to Embodiment 1.1 having the formula (7):

wherein p is 0, 1 or 2; q is 1 or 2;

X is C or N; Z is CH₂, N, or O;

R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; SO₃R⁵; R² can be independently H, halo, CN, OH, C₁₋₃alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅alkenyl, optionally substituted C₁₋₅alkynyl, optionally substituted C₂₋₆ cycloalkyl, optionally substituted C₂₋₆ cycloalkenyl; R⁵, R⁶ and R⁷ can be independently H, C₁₋₆ alkyl. 1.62 A compound according to Embodiments 1.54 or 1.55 wherein p, q, X, Z, Y, R¹, R², R³ and R⁴ are as defined in any one of Embodiments 1.1 to 1.53. 1.63 A compound according to Embodiment 1.1 which is as defined in any one of Examples 1-1 to 8-4. 1.64 A compound according to any one of Embodiments 1.1 to 1.62 having a molecular weight of less than 550, for example less than 500, or less than 450. 1.65 A compound according to any one of Embodiments 1.1 to 1.64 which is in the form of a salt. 1.66 A compound according to Embodiment 1.65 wherein the salt is an acid addition salt. 1.67 A compound according to Embodiment 1.65 or Embodiment 1.66 wherein the salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicated otherwise.

The term “treatment”, in relation to the uses of the compounds of the formulas (1) to (7), is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term “treatment” covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example in relation to methods of treatment of a disease or condition) refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain.

The term “non-aromatic hydrocarbon group” (as in “C₁₋₅ non-aromatic hydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group” refers to a group consisting of carbon and hydrogen atoms and which contains no aromatic rings. The hydrocarbon group may be fully saturated or may contain one or more carbon-carbon double bonds or carbon-carbon triple bonds, or mixtures of double and triple bonds. The hydrocarbon group may be a straight chain or branched chain group or may consist of or contain a cyclic group. Thus the term non-aromatic hydrocarbon includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” and “cycloalkenyl” are used in their conventional sense (e.g. as defined in the IUPAC Gold Book) unless indicated otherwise.

The term “cycloalkyl” as used herein, where the specified number of carbon atoms permits, includes both monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and bicyclic and tricyclic groups. Bicyclic cycloalkyl groups include bridged ring systems such as bicycloheptane, bicyclooctane and adamantane.

In the definitions of R¹, R², R³ and R⁴ above, where stated, one or two but not all, carbon atoms of the non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof. It will be appreciated that when a carbon atom is replaced by a heteroatom, the lower valencies of the heteroatoms compared to carbon means that fewer atoms will be bonded to the heteroatoms than would have been bonded to the carbon atom that has been replaced. Thus, for example, replacement of a carbon atom (valency of four) in a CH₂ group by oxygen (valency of two) will mean that the resulting molecule will contain two less hydrogen atoms and replacement of a carbon atom (valency of four) in a CH₂ group by nitrogen (valency of three) will mean that the resulting molecule will contain one less hydrogen atom.

Examples of a heteroatom replacements for carbon atoms include replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen or sulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—, replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to give a nitrile (cyano) group CH₂—C≡N, replacement of a carbon atom in a group —CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of a carbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide —CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atom in a —CH₂—CH₂—CH₂-chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—, replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen to give an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid) —CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom of the hydrocarbon group must remain.

Salts

Many compounds of the formulas (1) to (7) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formulas (1) to (7) include the salt forms of the compounds as defined in Embodiments 1.70 to 1.72.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

Acid addition salts (as defined in Embodiment 1.70) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts falling within Embodiment 1.71 include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

Where the compounds of the formula (1) contain an amine function, these may form quaternary ammonium salts (Embodiment 1.72), for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (1).

The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms but which differ only in the three-dimensional orientations of their atoms in space. The stereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the different orientations of an atom or group about a double bond, as in cis and trans (Z and E) isomerism about a carbon-carbon double bond, or cis and trans isomers about an amide bond, or syn and anti isomerism about a carbon nitrogen double bond (e.g. in an oxime), or rotational isomerism about a bond where there is restricted rotation, or cis and trans isomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.73), the invention provides a geometric isomer of a compound according to any one of Embodiments 1.1 to 1.72.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to the compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.74) the invention provides a compound according to any one of Embodiments 1.1 to 1.73 which contains a chiral centre.

The optical isomers may be characterised and identified by their optical activity (i.e. as + and − isomers, or d and l isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (−)-malic acid, and (−)-camphorsulphonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.75), the invention provides compositions containing a compound according to Embodiment 1.74 having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment 1.73 is present as a single optical isomer (e.g. enantiomer or diastereoisomer).

In one general embodiment (Embodiment 1.76), 99% or more (e.g. substantially all) of the total amount of the compound (or compound for use) of Embodiment 1.74 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.77) the compound is present as a single enantiomer.

In another embodiment (Embodiment 1.78), the compound is present as a single diastereoisomer.

The invention also provides mixtures of optical isomers, which may be racemic or non-racemic. Thus, the invention provides:

1.79 A compound according to Embodiment 1.74 which is in the form of a racemic mixture of optical isomers. 1.80 A compound according to Embodiment 1.74 which is in the form of a non-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1 to 1.80 may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O.

In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment of the invention (Embodiment 1.81), the compound of any one of Embodiments 1.1 to 1.80 contains no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment (Embodiment 1.82), however, the compound of any one of Embodiments 1.1 to 1.80 may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to 1.82 may form solvates. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.83 and 1.84, the invention provides:

1.83 A compound according to any one of Embodiments 1.1 to 1.82 in the form of a solvate. 1.84 A compound according to Embodiment 1.83 wherein the solvate is a hydrate.

For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA, 1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of the invention may be anhydrous. Therefore, in another embodiment (Embodiment 1.85), the invention provides a compound as defined in any one of Embodiments 1.1 to 1.83 in an anhydrous form (e.g. anhydrous crystalline form).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.83 may exist in a crystalline or non-crystalline (e.g. amorphous) state. Whether or not a compound exists in a crystalline state can readily be determined by standard techniques such as X-ray powder diffraction (XRPD). Crystals and their crystal structures can be characterised using a number of techniques including single crystal X-ray crystallography, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infra red spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR). The behaviour of the crystals under conditions of varying humidity can be analysed by gravimetric vapour sorption studies and also by XRPD. Determination of the crystal structure of a compound can be performed by X-ray crystallography which can be carried out according to conventional methods such as those described herein and as described in Fundamentals of Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F. Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union of Crystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b), 0-19-85579-2 (h/b)). This technique involves the analysis and interpretation of the X-ray diffraction of single crystal. In an amorphous solid, the three dimensional structure that normally exists in a crystalline form does not exist and the positions of the molecules relative to one another in the amorphous form are essentially random, see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.86 A compound according to any one of Embodiments 1.1 to 1.85 in a crystalline form. 1.80 A compound according to any one of Embodiments 1.1 to 1.85 which is: (a) from 50% to 100% crystalline, and more particularly is at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example 100% crystalline. 1.88 A compound according to any one of Embodiments 1.1 to 1.85 which is in an amorphous form.

Prodrugs

The compounds of the formula (1) as defined in any one of Embodiments 1.1 to 1.82 may be presented in the form of a pro-drug. By “prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1), as defined in any one of Embodiments 1.1 to 1.82.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (—C(═O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any hydroxyl groups present in the parent compound with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.89), the invention provides a pro-drug of a compound as defined in any one of Embodiments 1.1 to 1.82 wherein the compound contains a functional group which is convertible under physiological conditions to form a hydroxyl group or amino group.

Complexes and Clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.89 are complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds of Embodiments 1.1 to 1.89.

Accordingly, in another embodiment (Embodiment 1.90), the invention provides a compound according to any one of Embodiments 1.1 to 1.89 in the form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁ and/or M₄ receptor agonists. The muscarinic activity of the compounds can be determined using the Phospho-ERK1/2 assay described in Example A below.

A significant advantage of compounds of the invention is that they are highly selective for the M₁ and/or M₄ receptors relative to the M₂ and M₃ receptor subtypes. Compounds of the invention are neither agonists nor antagonists of the M₂ and M₃ receptor subtypes. For example, whereas compounds of the invention typically have pEC₅₀ values of at least 6 (preferably at least 6.5) and E_(max) values of greater than 80 (preferably greater than 95) against the M₁ and/or M₄ receptor in the functional assay described in Example A, they may have pEC₅₀ values of less than 5 and E_(max) values of less than 20% when tested against the M₂ and M₃ subtypes in the functional assay of Example A.

Some compounds of the invention have activity at both the M₁ and M₄ receptors, and some have activity at the M₄ receptor.

Accordingly, in Embodiments 2.1 to 2.15, the invention provides:

The compounds of the present invention have activity as muscarinic M₁ and/or M₄ receptor agonists. The muscarinic activity of the compounds can be determined using the Phospho-ERK1/2 assay described in Example A below.

2.1 A compound according to any one of Embodiments 1.1 to 1.90 for use in medicine. 2.2 A compound according to any one of Embodiments 1.1 to 1.90 for use as a muscarinic M₁ and/or M₄ receptor agonist. 2.3 A compound according to any one of Embodiments 1.1 to 1.90 which is a muscarinic M₁ receptor agonist having a pEC₅₀ greater than 6.9 and an E_(max) of at least 80 against the M₁ receptor in the assay of Example A herein or an assay substantially similar thereto. 2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁ receptor agonist having a pEC₅₀ greater than 7.0. 2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having an E_(max) of at least 90 against the M₁ receptor. 2.6 A compound according to any one of Embodiments 1.1 to 1.90 which is a muscarinic M₁ and M₄ receptor agonist having a pEC₅₀ in the range from 6.0 to 8.8 and an E_(max) of at least 70 against the M₄ receptor in the assay of Example A herein or an assay substantially similar thereto. 2.7 A compound according to any one of Embodiments 1.1 to 1.90 which is a muscarinic M₄ receptor agonist having a pEC₅₀ greater than 7.0. 2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having an E_(max) of at least 90 against the M₄ receptor. 2.9 A compound according to any one of Embodiments 2.3 to 2.8 which is selective for the M₁ and M₄ receptor compared to the muscarinic M₂ and M₃ receptors. 2.10 A compound according to Embodiment 2.9 which is selective for the M₄ receptor compared to the muscarinic M₂ and M₃ receptors. 2.11 A compound according to any one of Embodiments 2.3 to 2.5 which is selective for the M₁ receptor compared to the muscarinic M₂, M₃ and M₄ receptors. 2.12 A compound according to any one of Embodiments 2.3 to 2.8 which is selective for the M₄ receptor compared to the muscarinic M₁, M₂ and M₃ receptors. 2.13 A compound according to any one of Embodiments 2.3 to 2.12 which has a pEC₅₀ of less than 5 and an E_(max) of less than 50 against the muscarinic M₂ and M₃ receptor subtypes. 2.14 A compound according to Embodiment 2.13 which has a pEC₅₀ of less than 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ and M₃ receptor subtypes. 2.15 A compound according to any one of Embodiments 1.1 to 1.90 and Embodiments 2.3 to 2.14 for use in the treatment of a disease or condition mediated by the muscarinic M₁ and/or M₄ receptors.

By virtue of their muscarinic M₁ and/or M₄ receptor agonist activity, compounds of the invention can be used in the treatment of Alzheimer's disease, schizophrenia and other psychotic disorders, cognitive disorders and other diseases mediated by the muscarinic M₁ and/or M₄ receptor, and can also be used in the treatment of various types of pain.

Accordingly, in Embodiments 2.16 to 2.35, the invention provides:

2.16 A compound according to any one of Embodiments 1.1 to 1.90 for use in the treatment of a cognitive disorder or psychotic disorder. 2.17 A compound for use in according to Embodiment 2.16 wherein the cognitive disorder or psychotic disorder comprises, arises from or is associated with a condition selected from cognitive impairment, Mild Cognitive Impairment, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, presenile dementia, senile dementia, Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia, mania, Tourette's syndrome, Alzheimer's disease, progressive supranuclear palsy, impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as multi-infarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders; cognitive disorders due to drug abuse or drug withdrawal including nicotine, cannabis, amphetamine, cocaine, Attention Deficit Hyperactivity Disorder (ADHD) and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias, schizophrenia, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid, hallucinogenic and delusional disorders, personality disorders, obsessive compulsive disorders, schizotypal disorders, delusional disorders, psychosis due to malignancy, metabolic disorder, endocrine disease or narcolepsy, psychosis due to drug abuse or drug withdrawal, bipolar disorders and schizo-affective disorder. 2.18 A compound according to any one of Embodiments 1.1 to 1.90 for use in the treatment of Alzheimer's disease and/or dementia with Lewy bodies. 2.19 A compound according to any one of Embodiments 1.1 to 1.90 for use in the treatment of Schizophrenia. 2.20 A method of treatment of a cognitive disorder in a subject (e.g. a mammalian patient such as a human, e.g. a human in need of such treatment), which method comprises the administration of a therapeutically effective dose of a compound according to any one of Embodiments 1.1 to 1.90. 2.21 A method according to Embodiment 2.20 wherein the cognitive disorder comprises, arises from or is associated with a condition as defined in Embodiment 2.17. 2.22 A method according to Embodiment 2.21 wherein the cognitive disorder arises from or is associated with Alzheimer's disease. 2.23 A method according to Embodiment 2.22 wherein the cognitive disorder is Schizophrenia. 2.24 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the manufacture of a medicament for the treatment of a cognitive disorder. 2.25 The use according to Embodiment 2.24 wherein the cognitive disorder comprises, arises from or is associated with a condition as defined in Embodiment 2.17. 2.26 The use according to Embodiment 2.25 wherein the cognitive disorder arises from or is associated with Alzheimer's disease. 2.27 The use according to Embodiment 2.26 wherein the cognitive disorder is Schizophrenia. 2.28 A compound according to any one of Embodiments 1.1 to 1.90 for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain. 2.29 A method of treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain, which method comprises the administration of a therapeutically effective dose of a compound according to any one of Embodiments 1.1 to 1.90. 2.30 A compound according to any one of Embodiments 1.1 to 1.90 for the treatment of peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjogren's Syndrome. 2.31 A method of treatment of peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjogren's Syndrome, which method comprises the administration of a therapeutically effective dose of a compound according to any one of Embodiments 1.1 to 1.90. 2.32 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the manufacture of a medicament for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain or for the treatment of peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjogren's Syndrome. 2.33 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the use in the treatment of skin lesions for example due to pemphigus vulgaris, dermatitis herpetiformis, pemphigoid and other blistering skin conditions. 2.34 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the use in treating, preventing, ameliorating or reversing conditions associated with altered gastro-intestinal function and motility such as functional dyspepsia, irritable bowel syndrome, gastroesophageal acid reflux (GER) and esophageal dysmotility, symptoms of gastroparesis and chronic diarrhea. 2.35 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the use in the treatment of olfactory dysfunction such as Bosma-Henkin-Christiansen syndrome, chemical poisoning (e.g. selenium and silver), hypopituitarism, Kallmann Syndrome, skull fractures, tumour therapy and underactive thyroid gland. 2.36 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the treatment of addiction. 2.37 The use of a compound according to any one of Embodiments 1.1 to 1.90 for the treatment of movement disorders such as Parkinson's disease, ADHD, Huntingdon's disease, tourette's syndrome and other syndromes associated with dopaminergic dysfunction as an underlying pathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance with synthetic methods well known to the skilled person and as described herein.

Accordingly, in another embodiment (Embodiment 3.1), the invention provides a process for the preparation of a compound as defined in any one of Embodiments 1.1 to 1.90, which process comprises:

(A) the reaction of a compound of the formula (10)

with a compound of the formula (11):

under reductive amination conditions; wherein R¹, R², R³, R⁴, p, q, r and s are as defined in any one of Embodiments 1.1 to 1.90; or (B) the reaction of a compound of the formula (12):

with a compound of the formula Cl—C(═O)—CH₂—R⁴, in the presence of a base; or (C) the reaction of a compound of the formula (10)

with a compound of the formula (13):

under nucleophilic substitution conditions; wherein R¹, R², R³, R⁴, Y, p, q, r and s are as defined in any one of Embodiments 1.1 to 1.90; and optionally: (D) converting one compound of the formula (1) to another compound of the formula (1).

In process variant (A), the piperidine heterocycle (10) is reacted with the substituted ketone (11) under reductive amination conditions. The reductive amination reaction is typically carried out at ambient temperature using a borohydride reducing agent such as sodium triacetoxy-borohydride in a solvent such as dichloromethane or dichloroethane containing acetic acid.

In process variant (C), the piperidine heterocycle (10) is reacted with the sulfonic ester (13, R=methyl or 4-methylbenzyl) in a nucleophilic substitution reaction which is typically carried out with mild heating (e.g. to a temperature of from about 40° C. to about 70° C.) either neat, with no solvent, or in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylacetamide

Intermediate compounds of the formula (12) can be prepared by the series of reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine heterocycle (10) is reacted with the Boc-protected spiroketone (14) under reductive amination conditions. The reductive amination reaction is typically carried out with mild heating (e.g. to a temperature of from about 40° C. to about 70° C.) in the presence of either sodium cyanoborohydride in combination with zinc chloride or sodium triacetoxyborohydride in combination with titanium isopropoxide in a solvent such as dichloromethane or dichloroethane containing acetic acid to give an intermediate piperidine compound (15) which is then deprotected by removal of the Boc group by treatment with acid (e.g. trifluoroacetic acid in dichloromethane) to give the compound (12).

Compounds of the formula (12) can also be prepared by the sequence of reactions shown in Scheme 2 below.

In Scheme 2, the Boc-protected spiroketone (14) is reduced to the alcohol (16) using sodium borohydride in methanol. The alcohol (16) is then activated as the sulfonic ester (17, R=methyl or 4-methylbenzyl) using the corresponding sulfonyl chloride in dichloromethane in the presence of a tertiary amine such as triethylamine or N,N-diisopropylethylamine. The sulfonic ester (17) is reacted with the piperidine heterocycle (10) in a nucleophilic substitution reaction which is typically carried out with heating (e.g. to a temperature from about 40° C. to about 110° C.) either neat, with no solvent, or in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylacetamide to give compound (15), which is then deprotected by removal of the Boc group by treatment with acid (e.g. trifluoroacetic acid in dichloromethane) to give the compound (12).

Once formed, one compound of the formula (1), or a protected derivative thereof, can be converted into another compound of the formula (1) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic Chemistry and Organic Syntheses (see references above) or Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallisation and chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention, there is provided a pharmaceutical composition comprising at least one compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.82 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tablet composition.

In another embodiment (Embodiment 4.3), the composition is a capsule composition.

The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95%, preferably % (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragées, powders, tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow release tablets would in addition typically contain 0-99% (w/w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.

The compounds of the formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Examples 1-1 to 8-4

The compounds of Examples 1-1 to 8-4 shown in Table 1 below have been prepared. Their NMR and LCMS properties and the methods used to prepare them are set out in Table 3. The starting materials for each of the Examples are listed in Table 2.

TABLE 1

Example 1-1

Example 2-1

Example 2-2

Example 2-3

Example 2-4

Example 2-5

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 3-5

Example 3-6

Example 3-7

Example 3-8

Example 3-9

Example 4-1

Example 4-2

Example 4-3

Example 4-4

Example 4-5

Example 4-6

Example 4-7

Example 4-8

Example 4-9

Example 4-10

Example 4-11

Example 4-12

Example 4-13

Example 4-14

Example 4-15

Example 4-16

Example 4-17

Example 4-18

Example 4-19

Example 4-20

Example 4-21

Example 4-22

Example 4-23

Example 4-24

Example 4-25

Example 4-26

Example 4-27

Example 4-28

Example 4-29

Example 4-30

Example 4-31

Example 4-32

Example 4-33

Example 4-34

Example 4-35

Example 4-36

Example 4-37

Example 4-38

Example 4-39

Example 4-40

Example 4-41

Example 4-42

Example 4-43

Example 4-44

Example 4-45

Example 4-46

Example 4-47

Example 4-48

Example 5-1

Example 5-2

Example 6-1

Example 6-2

Example 6-3

Example 6-4

Example 6-5

Example 6-6

Example 6-7

Example 6-8

Example 6-9

Example 6-10

Example 6-11

Example 6-12

Example 7-1

Example 8-1

Example 8-2

Example 8-3

Example 8-4

GENERAL PROCEDURES

Where no preparative routes are included, the relevant intermediate is commercially available. Commercial reagents were utilized without further purification. Room temperature (rt) refers to approximately 20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker, Varian or Jeol instrument. Chemical shift values are expressed in parts per million (ppm), i.e. (δ)-values. The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=triplet of triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets, ddt=doublet of doublet of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. TLC for monitoring reactions refers to TLC run using the specified mobile phase and Silica gel F254 (Merck) as a stationary phase. Microwave-mediated reactions were performed in Biotage Initiator or CEM Discover microwave reactors.

LCMS experiments were typically carried out using electrospray conditions as specified for each compound under the following conditions:

LCMS Methods A and B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or Method B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mL H₂O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method C

Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent 6120B Single Quadrupole MS with API-ES Source; Column: Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A (%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents: solvent A=2.5 L H₂O+2.5 mL of (28% NH3 in H₂O); solvent B=2.5 L MeCN+129 mL H₂O+2.7 mL of (28% NH₃ in H₂O); Injection volume 0.5 μL; UV detection 190 to 400 nM; column temperature 40° C.; Flow rate 1.5 mL/min.

LCMS Methods D and E

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method D: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or Method E: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 L H₂O+2.5 mL 28% ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mL H₂O+2.5 mL 28% ammonia in H₂O solution); Injection volume 1 μL; UV detection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and −ve electrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method F:

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector; Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5; Solvents: solvent A=5 mM Ammonium acetate and 0.1% formic acid in H₂O; solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection 200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); column at ambient temperature; Flow rate 0.5 mL/min.

LCMS Method G:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10; Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method H:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100; Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method I:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 3.5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 5.00/90, 5.80/95, 10/95; Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method J:

Instruments: Agilent 1260 Infinity series UHPLC, ELSD: Agilent 1260 infinity, Column: XBridge Shield RP-18, 5 micron, 2.1×50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 0.5/2, 1.00/20, 4.00/92, 5.00/92, 5.50/50, 6.00/2; Solvents: A=5 mM ammonium acetate in water; solvent B=acetonitrile; Injection volume 1 μL; Detection by ELSD, Column temperature 35° C.: Flow rate 0.6 mL per/min.

LCMS Method K:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column: X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100; Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method L:

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1×100 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90, 9.00/10, 10.00/10; Solvents: solvent A=0.1% trifluoroacetic acid in water; solvent B=acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30° C.; Flow rate 0.3 mL per min

LCMS Method P:

Instruments: Agilent 1260 Infinity series UHPLC, ELSD: Agilent 1260 infinity, Column: Xbridge Shield RP-18, 5 micron, 2.1×50 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/2, 0.5/2, 1.00/20, 4.00/92, 5.00/92, 5.50/50, 6.00/2; Solvents: A=5 mM ammonium acetate in water; solvent B=acetonitrile; Injection volume 1 μL; Detection by ELSD, Column temperature 35° C.: Flow rate 0.6 mL per/min.

LCMS data in the experimental section are given in the format: Mass ion, retention time, UV activity.

ABBREVIATIONS

-   d=day(s) -   DCE=dichloroethane -   DCM=dichloromethane -   DEA=diethylamine -   DIPEA=diisopropylethylamine -   DMF=dimethylformamide -   DMSO=dimethylsulfoxide -   DPPA=diphenylphosphorylazide -   ES=electro spray ionisation -   Et₃N=triethylamine -   EtOAc=ethyl acetate -   h=hour(s) -   HPLC=high performance liquid chromatography -   LC=liquid chromatography -   LiHMDS=Lithium bis(trimethylsilyl)amide -   MeCN=acetonitrile -   MeOH=methanol -   min=minute(s) -   MS=mass spectrometry -   N₂=nitrogen -   NMR=nuclear magnetic resonance -   rt=room temperature -   sat.=saturated -   sol.=solution -   STAB=sodium triacetoxyborohydride -   TBAF=tetra butyl ammonium fluoride -   THF=tetrahydrofuran -   TLC=thin layer chromatography     Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,     secondary, iso, and tertiary.

SYNTHESIS OF INTERMEDIATES

Route 1

Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 3, 1-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved in DMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (5.0 g, 19.60 mmol) was dissolved in THF (50 mL) then 1.0M TBAF in THF (25.5 mL, 25.5 mmol) was added drop wise to reaction mixture followed by 1-nitropropane (2.62 g, 29.4 mmol), the reaction mixture was heated to 70° C. for 24 h. Reaction mixture was poured onto ice cold water (150 mL), extracted by EtOAc (500 mL), aqueous layer was further extracted with EtOAc (2×250 mL), organic layers were combined and dried (Na₂SO₄). Solvents were removed in vacuo and the residue was purified by column chromatography (normal phase silica, 0 to 6% EtOAc in Hexane) to give tert-butyl 4-(2-methoxy-2-oxoethyl)-4-(1-nitropropyl) piperidine-1-carboxylate (1.1 g, 40.9%) as yellow oil.

LCMS (Method F): m/z 345 (M+H)⁺ (ES⁺), at 2.43 min, UV inactive

tert-Butyl 4-(2-methoxy-2-oxoethyl)-4-(1-nitropropyl)piperidine-1-carboxylate (0.7 g, 2.03 mmol) was dissolved in MeOH (15 mL) and Raney®-Nickel (140.0 mg, 20% w/w) was added. The reaction mixture was purged with H₂ gas and then stirred at rt for 16 h. The reaction mixture was filtered through celite and solvents were removed in vacuo to give tert-butyl 1-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.28 g, 48.0%) as white solid.

LCMS (Method F): m/z 283 (M+H)⁺ (ES⁺), at 1.95 min, UV inactive tert-Butyl 1-ethyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.27 g, 0.96 mmol) was dissolved 4.0 M HCl in 1,4-dioxane (5.0 mL) at room temperature. The reaction mixture was stirred at rt for 16 h and then solvents were removed in vacuo. Residue was triturated with diethyl ether to give 1-ethyl-2,8-diazaspiro[4.5]decan-3-one.HCl, Intermediate 3 (0.15 g, 84.7%) as white solid.

The data for the title compound are in Table 2

Route 2

Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 6, 6-fluoro-2,8-diazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 0.18 g, 4.6 mmol) was suspended in THF (12 mL) and methyl 2-(dimethoxyphosphoryl)acetate (0.84 g, 4.6 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h then tert-butyl-3-fluoro-4-oxo-piperidine-1-carboxylate (1.0 g, 4.6 mmol) in THF (5 mL) was added drop wise at 0° C. The reaction mixture was stirred at rt for 16 h, then quenched with water (10 mL). The reaction mixture was extracted with EtOAc (3×20 mL), the organic layers were combined and washed and washed with sat. NaHCO₃ sol. (20 mL) and brine (20 mL) then dried (Na₂SO₄). The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 35% EtOAc in Isohexane]) to give tert-butyl 3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (0.94 g, 75%).

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.39 (d, J=2.5 Hz, 9H), 2.20-2.35 (m, 1H), 2.74-2.96 (m, 2H), 3.64 (d, J=2.0 Hz, 3H), 4.02-4.20 (m, 1H), 4.22-4.43 (m, 1H), 5.05 (ddd, J=47.5, 4.5, 3.5 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 0.5H), 6.31 (s, 0.5H)

tert-Butyl 3-fluoro-4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (0.94 g, 3.5 mmol) and nitromethane (0.32 g, 5.2 mmol) were dissolved in 1.0 M TBAF in THF (10 mL), the reaction mixture was heated at 50° C. under N₂ for 2 d. The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 40% EtOAc in Isohexane]) to give tert-butyl 3-fluoro-4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate (0.47 g, 41%).

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.37 (s, 9H), 1.59-1.74 (m, 2H), 2.62-2.71 (m, 1H), 2.71-2.83 (m, 1H), 2.94-3.08 (m, 1H), 3.16-3.28 (m, 1H), 3.60 (s, 3H), 3.66-3.84 (m, 1H), 3.94-4.07 (m, 1H), 4.64-4.71 (m, 1H), 4.71-4.86 (m, 2H)

tert-Butyl 3-fluoro-4-(2-methoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1-carboxylate (0.47 g, 1.41 mmol) was dissolved in EtOH (50 mL) and passed three times through an H-cube fitted with a ThalesNano CatCart® catalyst cartridge system, 70 mm Raney nickel (THS01132) at 40 Bar and 50° C. The solvents were removed in vacuo to give tert-butyl 6-fluoro-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.35 g, 85%) as a white solid which was used without further purification.

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.37 (s, 9H), 1.42-1.56 (m, 1H), 1.56-1.74 (m, 1H), 2.12 (s, 2H), 2.84-2.92 (m, 1H), 2.94-3.06 (m, 1H), 3.06-3.21 (m, 1H), 3.28 (d, J=9.5 Hz, 1H), 3.71-3.83 (m, 1H), 3.83-4.02 (m, 1H), 4.41-4.60 (m, 1H), 7.58-7.70 (m, 1H)

tert-Butyl 6-fluoro-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.35 g, 1.27 mmol) was suspended in 4.0M HCl in 1,4-dioxane (10 mL) and stirred at rt for 16 h. T The solvents were removed in vacuo to give 6-fluoro-2,8-diazaspiro[4.5]decan-3-one.HCl, Intermediate 6 (0.27 g, assume 100%) as a white solid which was used without further purification.

The data for the title compound are in Table 2

Route 3

Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 11, 4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one

2-Bromo-2-methylpropionic acid ethyl ester (15.4 g, 79.2 mmol) was dissolved in Et₂O (100 mL) and cooled to −78° C. under N₂. n-Butyl lithium (99 mL, 158 mmol) was added drop wise and the reaction mixture was allowed to stir at −78° C. for 1 h. N-benzyl-4-piperidone (10 g, 52.8 mmol) in Et₂O (100 mL) was added drop wise and the reaction mixture was stirred at −60° C. for 2 h. The reaction mixture was quenched with sat. NH₄Cl sol. (200 mL) and then diluted with water (500 mL). The reaction mixture was extracted with EtOAc (3×200 mL), the organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase, neutral silica gel, 60-120 mesh, 0 to 15% EtOAc in Hexane) to give ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanoate (12.0 g, 74.3%) as a yellow gum

LCMS (Method F): m/z 306 (M+H)⁺ (ES⁺), at 1.79 min, UV active

Ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanoate (12.0 g, 39.3 mmol) and 85% hydrazine hydrate (80 mL) were dissolved in EtOH (30 mL). The reaction mixture was refluxed at 100° C. for 120 h. The solvent was removed in vacuo to give 2-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanehydrazide (15.0 g, 131%) as a yellow gum, which was used crude in the next step.

LCMS (Method F): m/z 292 (M+H)⁺ (ES⁺), at 1.37 min, UV active

2-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-methylpropanehydrazide (15 g, assumed 39.3 mmol) was dissolved in water (60 mL) and then acidified with conc HCl (5 mL), the reaction mixture was cooled to 5° C. NaNO₂ (4.2 g, 61.8 mmol) in water (8 mL) was added at 0° C. and the reaction mixture was warmed to 60° C. for 1 h. The reaction mixture was basified with 20% NaOH solution and diluted with water (500 mL), extracted with EtOAc (3×200 mL), the organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase, neutral silica gel, 60-120 mesh, 0 to 2% MeOH in DCM) to give 8-benzyl-4, 4-dimethyl-1-oxa-3,8-diazaspiro [4.5]decan-2-one (5.0 g, 46.4%[over two steps]) as a yellow solid.

LCMS (Method F): m/z 275 (M+H)⁺ (ES⁺), at 1.50 min, UV active

8-Benzyl-4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (5.0 g, 18.2 mmol) was dissolved in MeOH (30 mL). 10% Pd/C (0.5 g) was added and the reaction mixture was stirred under H₂ atmosphere (1 atm) at 50° C. for 2 h. The reaction mixture was filtered through celite and the solvents was removed in vacuo. The residue was triturated with Et₂O to give 4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 12 (1.5 g, 45.4%) as a yellow solid.

The data for the title compound are in Table 2

Route 4

Typical Procedure for the Preparation of Piperidines, as Exemplified by the Preparation of Intermediate 13, 1-ethyl-1,2,8-triazaspiro[4.5]decan-3-one.HCl

Sodium hydride in mineral oil (60%, 11.9 g, 297 mmol) was dissolved in DMF (200 mL) and methyl 2-(dimethoxyphosphoryl)acetate (52.0 g, 286 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 20 min then tert-butyl 4-oxopiperidine-1-carboxylate (45.5 g, 228 mmol) in DMF (100 mL) was added drop wise at 0° C. The reaction mixture was stirred at rt for 2 h, then diluted with ice water (20 mL), filtered and the solvents were removed in vacuo to give tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (42.5 g, 72.9%) as a yellow solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 2.47 min, UV active

tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.0 g, 11.8 mmol) was dissolved in EtOH (20 mL) and hydrazine hydrate (85% sol., 1.1 mL, 23.5 mmol) was added and the reaction mixture was stirred at 80° C. for 8 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (120 mL), aqueous layer was further extracted with EtOAc (2×120 mL), organic layers were combined washed with brine (100 mL) and dried (Na₂SO₄). The solvents were removed in vacuo and the residue was purified by column chromatography (normal silica, mesh size: 60-120, 4.0% to 10.0% MeOH in DCM) to give tert-butyl 3-oxo-1, 2, 8-triazaspiro[4.5]decane-8-carboxylate (1.78 g, 59.3%) as white solid.

LCMS (Method F): m/z 256 (M+H)⁺ (ES⁺), at 1.70 min, UV inactive

tert-Butyl 3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (0.1 g, 0.39 mmol), was dissolved in MeOH (5 mL) and acetaldehyde (0.03 mL, 0.59 mmol) was added, the reaction mixture was stirred at 0° C. for 2 h. NaCNBH₃ (18 mg, 0.48 mmol) was added portion wise and the reaction mixture was stirred at rt for 7 h. The solvents were removed in vacuo and the residue was partitioned between H₂O (40 mL) and EtOAc (25 mL), aqueous layer was extracted with EtOAc (2×25 mL), the organic layers were combined, washed with brine (100 mL) and dried (Na₂SO₄). The solvents were removed in vacuo and the residue was purified by triturating with Hexane (3×3 mL) to give tert-butyl 1-ethyl-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate, Intermediate 86 (0.09 g, 80.9%) as a colourless gum.

The data for the title compound are in Table 2

tert-Butyl 1-ethyl-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.71 mmol) was dissolved in 1,4-dioxane (3 mL) and 4.0M HCl in 1,4-dioxane (10 mL) was added drop wise, the reaction mixture was stirred at 30° C. for 16 h. The solvents were removed in vacuo and the residue was purified by triturating with Et₂O (3×3 mL) to give 1-ethyl-1,2,8-triazaspiro[4.5]decan-3-one.HCl, Intermediate 13 (0.14 g, 90.3%) as a yellow solid.

The data for the title compound are in Table 2

Route 5

Typical Procedure for the Preparation of Ketones, as Exemplified by the Preparation of Intermediate 44, ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate

2-Boc-6-oxo-2-azaspiro[3.3]heptane (0.65 g, 3.08 mmol) was added portionwise to 4.0M HCl in 1,4-dioxane (3.1 ml, 12 mmol). After 24 h, the reaction was concentrated in vacuo and the residual solid dissolved in a mixture of NEt₃ (0.86 ml, 6.15 mmol) and DCM (13.5 ml). On completion of dissolution the solution was immediately cooled to 0° C., then ethyl chloroformate (0.32 ml, 3.38 mmol) was added dropwise. After 18 h, the mixture was poured into DCM (50 ml) and NaHCO₃ solution (50 ml) and extracted (2×50 ml). The organic layers were combined, washed with brine (10 ml), then dried over MgSO₄. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 10% MeOH in DCM]) to provide ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate as a colourless oil which solidified to needles on standing (0.17 g, 30%).

The data for the title compound are in Table 2

Route 6

Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Intermediate 48, 4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

To a solution of NaH (8.96 g, 50% in mineral oil, 186.9 mmol) in THF (160 mL), triethylphosphonoacetate (20.5 mL, 102.7 mmol) was added at 0° C. After stirring for 1 h at 0° C., picolinaldehyde (10.00 g, 93.4 mmol) was slowly added at 0° C. and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with H₂O (10 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried (Na₂SO₄) and the solvents were removed in vacuo. The crude residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 10% to 30% EtOAc in hexane] to give ethyl (E)-3-(pyridin-2-yl)acrylate (7.90 g, 49%) as a liquid.

m/z (ES⁺): 178 (M+H)⁺

To a solution of ethyl (E)-3-(pyridin-2-yl)acrylate (7.9 g, 23.0 mmol) in MeOH (100 mL), 10% Pd/C (0.80 g, 50% wet) was added and the reaction mixture was stirred under H₂ (1 atm) at rt for 16 h. The reaction mixture was filtered through a pad of celite, thoroughly washed with MeOH and the solvents were removed in vacuo to give ethyl 3-(pyridin-2-yl)propanoate (7.8 g, 98%) as a liquid.

m/z (ES⁺): 179 (M+H)⁺

To a solution ethyl 3-(pyridin-2-yl)propanoate (2.90 g, 16.2 mmol) in THF (60 mL), LiHMDS (1 M, 48.6 mL, 48.6 mmol) was slowly added at −78° C. and stirred for 30 min, followed by addition of 1-benzylpiperidin-4-one (3.10 g, 16.2 mmol) at −78° C. and the reaction mixture was stirred at −78° C. for 4 h. After completion, the reaction mixture was quenched with sat NH₄Cl solution (30 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined, dried (Na₂SO₄) and the solvents were removed in vacuo. The crude residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 10% to 30% EtOAc in hexane] to give ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoate (2.80 g, 50%) as a liquid.

m/z (ES⁺): 369 (M+H)⁺

To a solution of ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoate (2.80 g, 7.61 mmol) in MeOH: THF (1:1, 30 mL), LiOH.H₂O (1.28 g, 30.4 mmol) in water (10 mL), was added at rt and the reaction mixture was stirred for 16 h. The reaction mixture was acidified with glacial acetic acid and extracted with EtOAc (3×20 mL). The organic layers were combined and washed with brine, dried (Na₂SO₄) and the solvents were removed in vacuo to give 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoic acid (2.16 g, 84%) as a pale yellow solid.

m/z (ES⁺): 339 (M+H)⁺

To a solution of 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-(pyridin-2-yl)propanoic acid (1.70 g, 5.11 mmol) in toluene (30 mL) was added DPPA (1.32 mL, 6.13 mmol) and Et₃N (0.84 mL, 6.13 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient 1% to 30% EtOAc in hexane] to give 8-benzyl-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (1.25 g, 56%) as a white solid.

m/z (ES⁺): 338 (M+H)⁺

To a solution of 8-benzyl-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.80 g, 2.37 mmol) in MeOH (40 mL), after degassing under N₂, 10% Pd(OH)₂ on charcoal (0.15 g, 50% wet) was added. The reaction mixture was stirred under H₂ (1 atm) at rt for 16 h. After completion, the reaction mixture was filtered through a pad of celite, thoroughly washed with MeOH and the solvents were removed in vacuo to give 4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 48 (0.58 g, 98%) as a liquid.

The data for the title compound are in Table 2

Route 7

Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Intermediate 60, 4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

Diisopropyl amine (12.8 g, 126.98 mmol) was dissolved in THF (100 mL) and cooled to −78° C. under nitrogen. n-Butyl lithium (79.3 mL, 126.98 mmol, 1.6 M in THF) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h. Ethyl 4,4,4-trifluorobutanoate (16.2 g, 95.23 mmol) was added over 30 min then the reaction mixture was stirred at −78° C. for 1 h. N-benzyl piperidone (15 g, 79.36 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with a saturated solution of NH₄Cl (200 mL), diluted with water (500 mL) and extracted with EtOAc (3×200 mL), the combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 25% EtOAc in Hexane) to give ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanoate (24.0 g, 84.2%) as a yellow gum.

LCMS (Method F): m/z 360 (M+H)⁺ (ES⁺), at 1.75 min, UV active

Ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanoate (24.0 g, 66.85 mmol) and 85% hydrazine hydrate (200 mL) were dissolved in ethanol (100 mL). The reaction mixture was refluxed and allowed to stir at 100° C. for 72 h. The reaction mixture was concentrated in vacuo to give the crude product of 2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanehydrazide (28.0 g) as a yellow gum. The crude product was used in the next step without any purification.

LCMS (Method F): m/z 346 (M+H)⁺ (ES⁺), at 1.41 min, UV active

Crude 2-(1-benzyl-4-hydroxypiperidin-4-yl)-4,4,4-trifluorobutanehydrazide (28 g, 81.1 mmol) was dissolved in water (200 mL), acidified with conc HCl and cooled to 0° C. NaNO₂ (16.7 g, 243.2 mmol) in water (50 mL) was added at 0° C. and the reaction mixture was allowed to stir at 60° C. for 1 h. The reaction was basified with 20% NaOH solution, diluted with water (500 mL) and extracted with EtOAc (3×200 mL), the combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 3.0% MeOH in dichloromethane) to give 8-benzyl-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (1.2 g, 4.5%) as a yellow solid.

LCMS (Method F): m/z 329 (M+H)⁺ (ES⁺), at 1.48 min, UV active

8-Benzyl-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (1.2 g, 3.65 mmol) was dissolved in methanol (30 mL). Pd/C (300 mg, 10% Pd/C 50% moisture) was added and the reaction mixture was stirred under a hydrogen atmosphere (1 atm) at 50° C. for 2 h. The reaction mixture was filtered through celite and the solvents were removed in vacuo. The crude product was triturated with diethyl ether to give 4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 60 (0.75 g, 88.2%) as a yellow solid

The data for the title compound are in Table 2.

Route 8

Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Intermediate 76, tetrahydrospiro[piperidine-4,1′-pyrrolo[1,2-c][1,3]oxazol]-3′-one

tert-Butyl pyrrolidine-1-carboxylate (2.91 g, 17.0 mmol) was dissolved in THF (160 mL) and cooled to −78° C. 1.4 M s-BuLi in cyclohexane (14.29 mL, 20.0 mmol)) was added drop wise and allowed to stir at −78° C. for 3 h. Benzyl 4-oxopiperidine-1-carboxylate (3.96 g, 17.0 mmol) in THF (10 mL) was added over 30 min at −78° C., and then stirred at −78° C. for 5 h. The reaction was diluted with cold water (500 mL), extracted with EtOAc (3×150 mL), the combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 15% EtOAc in Hexane) to give benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.2 g, 23%) as a yellow liquid.

LCMS (Method F): m/z 406 (M+H)⁺ (ES⁺), at 2.41 min, UV active

Benzyl 4-(1-(tert-butoxycarbonyl) pyrrolidin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.2 g, 2.97 mmol) was dissolved in 1,4-dioxane (10 mL) and cooled to 0° C. 4.0 M HCl in 1,4-dioxane (10 mL) was added and the reaction mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo and the residue was triturated with diethyl ether (10 mL) to give benzyl 4-hydroxy-4-(pyrrolidin-2-yl)piperidine-1-carboxylate.HCl (178 mg, 17.6%) as a yellow gum.

LCMS (Method F): m/z 305 (M+H)⁺ (ES⁺), at 1.58 min, UV active

Benzyl 4-hydroxy-4-(pyrrolidin-2-yl) piperidine-1-carboxylate.HCl (170 mg, 0.56 mmol) and DIPEA (0.3 mL, 0.22 g, 1.68 mmol) were dissolved in THF (5 mL) and cooled to 0° C. Triphosgene (83.0 mg, 0.28 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal phase, Neutral alumina, 0 to 20% EtOAc in Hexane) to give benzyl 3′-oxotetrahydro-3′H-spiro[piperidine-4,1′-pyrrolo[1,2-c]oxazole]-1-carboxylate (175 mg, 94.5%) as a yellow gum.

LCMS (Method F): m/z 331 (M+H)⁺ (ES⁺), at 1.99 min, UV active

Benzyl 3′-oxotetrahydro-3′H-spiro[piperidine-4,1′-pyrrolo[1,2-c]oxazole]-1-carboxylate (170 mg, 0.515 mmol) was dissolved in methanol (5 mL). Pd/C (50% moisture) (50 mg) was added and the reaction mixture was stirred at 50° C. for 1 h under hydrogen at 1 atm. The reaction mixture was filtered through celite and the solvents were removed in vacuo to give crude tetrahydrospiro[piperidine-4,1′-pyrrolo[1,2-c][1,3]oxazol]-3′-one, Intermediate 76 (60 mg, 59.4%) as a yellow gum. The crude product was used directly without purification.

The data for the title compound are in Table 2.

Route 9

Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Intermediate 62, 4-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one

Ethyl 3-phenylpropionate (5.0 g, 28.0 mmol) was dissolved in diethyl ether (40 mL) and cooled to −78° C. under nitrogen. n-Butyl lithium (26.3 mL, 42.0 mmol) was added drop wise and the reaction mixture was stirred at −78° C. for 1 h. N-benzyl piperidone (3.5 g, 18.0 mmol) was added drop wise and the reaction mixture was stirred at −60° C. for 2 h. The reaction mixture was quenched with NH₄Cl (sat aq.) (200 mL) diluted with water (150 mL) and extracted with EtOAc (3×120 mL). The combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 15% EtoAc in Hexane) to give ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-phenylpropanoate (600 mg, 9.0%) as a yellow gum.

m/z (ES⁺): 368 (M+H)⁺

Ethyl 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-phenylpropanoate (600 mg, 1.63 mmol) and 85% hydrazine hydrate (10 mL) were dissolved in ethanol (2 mL). The reaction mixture was heated to 100° C. for 120 h. The reaction mixture was cooled to rt and the solvents were removed in vacuo to give 2-(1-benzyl-4-hydroxypiperidin-4-yl)-3-phenylpropanehydrazide (350 mg) as a white solid. The crude product was used directly in the next step.

LCMS (Method I): m/z 354 (M+H)⁺ (ES⁺), at 3.90 min, UV active.

2-(1-Benzyl-4-hydroxypiperidin-4-yl)-3-phenylpropanehydrazide (350 mg, 1.0 mmol) was dissolved in water (5 mL) and the reaction mixture was cooled to 0° C. and acidified with conc HCl. NaNO₂ (103 mg, 1.50 mmol) in water (2 mL) was added and the reaction was stirred at 60° C. for 1 h. The reaction mixture was basified with 20% NaOH solution, diluted with water (80 mL), extracted with EtOAc (3×60 mL). The combined organic layers were dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by triturating with hexane to give 4,8-dibenzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (235 mg, 70.5%) as a brown solid.

LCMS (Method K): m/z 337 (M+H)⁺ (ES⁺), at 4.78 min, UV active.

4,8-Dibenzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (230 mg, 0.69 mmol) was dissolved in methanol (15 mL). Pd/C (10 mol %) was added and the reaction mixture was stirred under hydrogen (1 atm) at 50° C. for 2 h. The reaction mixture was filtered through celite and the solvents were removed in vacuo. The residue was triturated with diethyl ether to give 4-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 62 (145 mg, 86.3%) as a white solid.

The data for the title compound are in Table 2.

Route 10

Typical Procedure for the Preparation of Piperidines as Exemplified by the Preparation of Intermediate 83, 3-cyclopropyl-4-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.1 mmol) in DMF (50 mL), triphenyl(propyl)phosphonium bromide (9.6 g, 25.1 mmol) and NaH (60% in mineral oil, 7.5 g, 150.7 mmol) were added at 0° C. and stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with hexane (3×50 mL). The combined organic layer was washed with brine (50 mL), dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by flash column chromatography (normal phase, silica gel, 100-200 mesh, gradient 0% to 30% EtoAc in Hexane) to give tert-butyl 4-propylidenepiperidine-1-carboxylate (1.2 g, 21%) as a colorless liquid.

m/z (ES⁺): 226

To a solution of tert-butyl 4-propylidenepiperidine-1-carboxylate (2 g, 8.88 mmol) in DCM (2 mL), mCPBA (2.9 g, 13.3 mmol) was added portion-wise at 0° C. and the mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was quenched with ice-cold water (40 mL) and extracted with DCM (3×20 mL). The combined organic layer was washed with 10% NaOH (20 mL), dried (Na₂SO₄) and the solvents were removed in vacuo to give tert-butyl 2-ethyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g, 93%) as a colorless liquid. This was used for the next step without further purification.

m/z (ES⁺): 242

To a solution of cyclopropanamine (0.8 mL, 12.4 mmol) in DCM (2 mL), AlMe₃ (2M solution in toluene, 6.2 mL, 12.4 mmol) was added drop-wise at 0° C. and the mixture was stirred at the same temperature for 30 min. tert-Butyl 2-ethyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1 g, 4.14 mmol) was added drop-wise at 0° C. and the mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was cooled to 0° C. and quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined organic layer was washed with brine (50 mL), dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by flash column chromatography (normal phase, silica gel, 100-200 mesh, gradient 2% to 5% methanol in DCM) to give tert-butyl 4-(1-(cyclopropylamino)propyl)-4-hydroxypiperidine-1-carboxylate (510 mg, 63%) as a faint yellow liquid.

m/z (ES⁺): 299

To a solution of tert-butyl 4-(1-(cyclopropylamino)propyl)-4-hydroxypiperidine-1-carboxylate (500 mg, 1.67 mmol) in dioxane (10 mL), DIPEA (0.9 mL, 5.03 mmol) was added drop-wise at 0° C. and the mixture was stirred at the same temperature for 20 min. Triphosgene (248 mg, 0.83 mmol) was added portion-wise at 0° C. and the reaction mixture was stirred at 110° C. for 16 h in a closed tube. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by flash column chromatography (normal phase, silica gel, 100-200 mesh, gradient 2% to 5% methanol in DCM) to give tert-butyl 3-cyclopropyl-4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (450 mg, 82%) as a faint yellow liquid.

m/z (ES+): 325

To a solution of tert-butyl 3-cyclopropyl-4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (450 mg, 1.38 mmol) in 1,4-dioxane (2 mL), HCl in dioxane (4M, 6 mL) was added at 0° C. and the mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo. The residue was basified with aq sat. NaHCO₃ (10 mL) and the solvents were removed in vacuo. To the crude reaction mass 5% MeOH/DCM (30 mL) was added and the mixture was filtered. The solvents were removed in vacuo to give 3-cyclopropyl-4-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, Intermediate 83, (300 mg, 96%) as a brown sticky liquid, which was used without further purification.

The data for the title compound are in Table 2.

Route 11

Typical Procedure for the Preparation of Piperidines Via Alkylation as Exemplified by the Preparation of Intermediate 87, 1-ethyl-2-(methyl-d3)-1,2,8-triazaspiro[4.5]decan-3-one.HCl.

To a solution of tert-butyl 1-ethyl-3-oxo-1, 2, 8-triazaspiro [4.5] decane-8-carboxylate (400 mg, 1.41 mmol) in acetonitrile (10 mL), Cs₂CO₃ (920 mg, 2.82 mmol) and methyl-d₃ iodide (204 mg, 1.41 mmol) were added. The reaction mixture was stirred at 30° C. for 8 h and then partitioned between H₂O (120 mL) and EtOAc (80 mL), the aqueous layer was further extracted with EtOAc (2×80 mL), the organic layers were combined, dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by column chromatography (Normal basic activated alumina, 15% to 20% EtOAc in Hexane) to give tert-butyl 1-ethyl-2-(methyl-d3)-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (210 mg, 49.5%) as a yellow gum.

LCMS (Method I): m/z 302 (M+H)⁺ (ES⁺), at 3.70 min, UV active.

To a solution of tert-butyl 1-ethyl-2-(methyl-d3)-3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (210 mg, 0.70 mmol) in 1,4-dioxane (5 mL). 4.0M HCl in 1,4-dioxane (2 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The solvents were removed in vacuo, and residue was purified by triturating with diethyl ether (3×2 mL) to give 1-ethyl-2-(methyl-d3)-1,2,8-triazaspiro[4.5]decan-3-one.HCl, Intermediate 87 (140 mg, 85.0%) as a yellow solid.

The data for the title compound are in Table 2.

General Synthetic Procedures:

Route a

Typical Procedure for the Preparation of Piperidines Via NaCNBH₃ Reductive Amination as Exemplified by the Preparation of Example 3-2, ethyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

2,8-diazaspiro[4.5]decan-3-one (0.51 g, 3.30 mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.650 g, 3.30 mmol) were dissolved in MeOH (50 mL) and zinc chloride (1.35 g, 9.90 mmol) was added. The reaction mixture was stirred at 50° C., under a nitrogen atmosphere, for 2 h. The reaction mixture was cooled to rt and NaCNBH₃ (0.42 g, 6.60 mmol) was added. The reaction mixture was stirred at 50° C. under nitrogen for 16 h. The reaction mixture was cooled to rt and treated with sat. NaHCO₃ sol., the organic solvent was removed in vacuo and the aqueous layer was extracted with DCM (2×10 mL) the organic layers were combined and washed with brine (10 mL) and dried by passing through a Biotage Phase Separator cartridge. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 40% MeOH in DCM]) to give an inseparable mixture of diastereomers. This mixture was purified by preparative reversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with 20 to 50% MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 205 nm) to give ethyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 3-2 Isomer 1 (0.101 mg, 9.0%) as a white solid and ethyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 3-2 Isomer 2 (0.099 g, 8.9%) as a white solid.

The data for Isomer 2 are in Table 3.

If a hydrochloride salt of the piperidine was used in this reaction sequence, then it was desalted with K₂CO₃ in water/methanol before undergoing the reductive amination reaction.

Route b

Typical Procedure for the Preparation of Piperidines Via NaCNBH₃ Reductive Amination as Exemplified by the Preparation of Example 4-7, ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

4-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (0.50 g 2.71 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.54 g, 2.71 mmol), Et₃N (0.82 g, 8.15 mmol), ZnCl₂ (0.06 mg, 0.41 mmol), were dissolved in MeOH (20 mL) under N₂ and stirred at 60° C. for 16 h. Reaction mixture cooled to 0° C. and NaCNBH₃ (0.51 g, 8.15 mmol) was added portion wise, the reaction mixture was stirred under N₂ at 60° C. for 16 h. The solvents were removed in vacuo and the residue was partitioned between water (50 mL) and EtOAc (60 mL), the aqueous layer was further extracted with EtOAc (2×60 mL); the organic layers were combined and washed with brine, then dried (Na₂SO₄). The solvents were removed in vacuo and the residue was purified by preparative reversed phase HPLC (X-Bridge (250×19 mm) 5μ, C18, 15 mL per min, gradient 25% to 100% (over 25 min) then 100% (5 min) 0.1% NH3 in MeCN/water) to give ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate as two separate diastereomeric racemic mixtures of isomers. Each mixture was further purified by chiral preparative reversed phase HPLC [CHIRAL PAK AD-H (250×20 mm) 5μ, C18, 20 mL per min, gradient 20% (over 20 min) 0.1% DEA in n-Hexane/MeOH:IPA (50:50)] to give ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-7 Isomer 1 (0.091 g, 9.1%) as a white solid, ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-7 Isomer 2 (0.088 g, 8.8%) as a white solid, ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-7 Isomer 3 (0.085 g, 8.6%) as a white solid and ethyl 2-(4-ethyl-2-oxo-1-oxa-3, 8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-7 Isomer 4 (0.087 g, 8.8%) as a white solid.

The data for all Isomers are in Table 3.

Route c

Typical Procedure for the Preparation of Piperidines Via Sodium Triacetoxyborohydride Reductive Amination as Exemplified by the Preparation of Example 4-10, ethyl 2-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (3.60 g, 19.6 mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (4.05 g, 20.5 mmol) were dissolved in DCM (196 mL) at rt and AcOH (2.52 mL, 36.6 mmol) was added. The reaction mixture was heated to reflux under N₂ for 16 h then cooled to rt. STAB (8.48 g, 40.0 mmol) was added, the reaction mixture was again heated to reflux for 16 h then cooled to rt. The reaction mixture was quenched with the addition of NaHCO₃ (sat aq.) (100 mL), solid Na₂CO₃ added to ensure aqueous layer was basic, reaction mixture extracted with DCM (4×100 mL). The organic layers were combined and washed with brine, then dried (MgSO₄). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 27 mL per min, gradient 0% to 10% MeOH in DCM]) to give an inseparable mixture of diastereomers. This mixture was purified by preparative reversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with 10 to 30% MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 205 nm) to give ethyl 2-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate Example 4-10 Isomer 1 1.57 g, 22.0%) as a colourless solid and ethyl 2-(4,4-dimethyl-2-oxo-1-oxa-3, 8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate Example 4-10 Isomer 2 (1.50 g, 21.0%) as a colourless solid.

The data for Isomer 2 are in Table 3.

For examples, such as Example 3-4, containing chiral isomers these were further purified by chiral preparative reversed phase HPLC [CHIRALPAK AD-H, 250×20 mm, 5 um, 20 mL per min, gradient 25.0% (over 28.0 mins), 0.1% DEA in Hexane/MeOH:IPA (50:50)].

Route d

Typical Procedure for the Preparation of Piperidines Via Carbamate Formation as Exemplified by the Preparation of Example 4-2, trideuteromethyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

CD₃OD (0.067 g, 1.91 mmol) was dissolved in an. THF (8 mL) and the solution was cooled to 0° C. under a nitrogen atmosphere. Sodium hydride in mineral oil (60%, 0.078 g, 1.91 mmol) was cautiously added and the mixture was stirred for 1 hour at 0° C. 4-nitrophenyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (0.205 g, 0.477 mmol) was added drop wise as a solution in an. THF (4 mL) with an. DMF (0.5 mL) at 0° C. and the reaction mixture was stirred at rt for 16 h). The reaction mixture was quenched with the addition of water (8 mL), and extracted with EtOAc (3×8 mL). The organic layers were combined, then dried (MgSO₄). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 12 mL per min, gradient 2% to 10% MeOH in DCM]) to give an inseparable mixture of diastereomers. This mixture was purified by preparative reversed phase HPLC [(Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with 20 to 50% MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 205 nm) to give trideuteromethyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-2 Isomer 1 (0.07 g, 5%) as a colourless oil and trideuteromethyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 4-2 Isomer 2 (0.07 g, 5%) as a colourless oil,

The data for Isomer 2 are in Table 3.

Route e

Typical Procedure for the Preparation of Piperidines Via N-Alkylation as Exemplified by the Preparation of Example 8-2, ethyl 6-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate

ethyl 6-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate (0.10 g, 0.27 mmol) was dissolved in DMF (1.0 mL). NaH (60%) (0.023 g, 0.58 mmol) was added at 0° C. and the reaction mixture was stir at 0° C. for 5 min. Ethyl iodide (0.07 g, 0.45 mmol) was added and the reaction mixture to stir at 0° C. for 30 min. The reaction mixture was quenched with the addition of water (25 mL) and extracted with EtOAc (25 mL), the aqueous layer was further extracted with EtOAc (2×25 mL); the organic layers were combined and washed with brine, then dried (Na₂SO₄). The solvents were removed in vacuo, and the residue was purified by preparative reversed phase HPLC [X-SELECT PHENYL HEXYL (150×19 mm) 5μ, C18, 20 mL per min, gradient 30% to 100% (over 12 min) then 100% (3 min), 0.02% NH3 in water and 100% in acetonitrile] to give ethyl 6-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, Example 8-2 (0.04 g, 37.1%) as a colourless solid.

The data for the title compound are in Table 3.

Route g

Typical Procedure for the Preparation of Piperidines Via Sodium Triacetoxyborohydride Reductive Amination as Exemplified by the Preparation of Example 4-19, ethyl 2-[2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate

To a solution of 4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (250 mg, 1.01 mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (185 mg, 1.01 mmol) in DCM (10 mL) was added Ti(O^(i)Pr)₄ (0.9 mL, 3.03 mmol), the reaction mixture was stirred at 0° C. for 40 min. STAB (640 mg, 3.03 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with NaHCO₃ (sat aq.) (10 mL). The aqueous layer was extracted with DCM (2×20 mL), the organic layers were combined and dried (Na₂SO₄) and the solvents were removed in vacuo. The residue was purified by preparative reversed phase HPLC [Symmetry Shield RP, C-18, 19×250 mm, 5μ, isocratic gradient 22% to 78% (over 25 min) then 100% (5 min) MeCN in water containing 5 mM ammonium bicarbonate] to give ethyl 2-[2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 4-19 Isomer 1 (25 mg, 6%) as a yellow solid and ethyl 2-[2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 4-19 Isomer 2 (36 mg, 9%) as a yellow solid.

The data for the title compound are in Table 3.

TABLE 2 Starting Materials and Intermediates Table 2 Inter- mediate Route Name Data 1 2,8-diazaspiro[4.5]decan-3- Commercially available, one CAS: 561314-57-6 2 Route 1 and 1-methyl-2,8- LCMS (Method F): m/z 169 intermediates diazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 4.65 min, 16 and 31 one.HCl UV inactive 3 Route 1 and 1-ethyl-2,8- LCMS (Method F): m/z 183 intermediates diazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 5.55 min, 16 and 32 one.HCl UV inactive 4 Route 1 and 1-propyl-2,8- LCMS (Method F): m/z 197 intermediates diazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 5.31 min, 16 and 33 one.HCl UV inactive 5 Route 1 and 1-benzyl-2,8- LCMS (Method F): m/z 245 intermediates diazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 1.47 min, 16 and 34 one.HCl UV active 6 Route 2 and 6-fluoro-2,8- LCMS (Method D): m/z 173 intermediates diazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 0.13 min, 17 and 30 one.HCl UV inactive 7 1-oxa-3,8- Commercially available, diazaspiro[4.5]decan-2- CAS: 2052-96-0 one.HCl 8 Route 3 and 4-methyl-1-oxa-3,8- LCMS (Method G): m/z 171 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺), at 4.31 min, 15 and 35 UV inactive 9 Route 3 and 4-ethyl-1-oxa-3,8- LCMS (Method G): m/z 185 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺), at 3.27 min, 15 and 36 UV inactive 10 Route 3 and 4-(propan-2-yl)-1-oxa-3,8- LCMS (Method G): m/z 199 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺), at 3.68 min, 15 and 37 UV inactive 11 Route 3 and 4,4-dimethyl-1-oxa-3,8- LCMS (Method G): m/z 185 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺), at 1.90 min, 15 and 38 UV active 12 1,3,8-triazaspiro[4.5]decan-2- Commercially available, one CAS: 561314-52-1 13 Route 4 and 1-ethyl-1,2,8- LCMS (Method H): m/z 184 intermediates triazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 4.15 min, 16 and 39 one.HCl UV inactive 14 Route 4 and 1-benzyl-1,2,8- LCMS (Method F): m/z 246 intermediates triazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 4.17 min, 16 and 40 one.HCl UV inactive 15 N-benzyl-4-piperidinone Commercially available, CAS: 3612-20-2 16 tert-butyl-4-oxopiperidine-1- Commercially available, carboxylate CAS: 79099-07-3 17 tert-butyl-3-fluoro-4-oxo- Commercially available, piperidine-1-carboxylate CAS: 211108-50-8 18 tert-butyl 2-oxo-6-azaspiro[3.4] Commercially available, octane-6-carboxylate 203661-71-6 19 Route 5 and 6-butanoyl-6- ¹H NMR: (400 MHz, intermediates azaspiro[3.4]octan-2-one DMSO-d₆) δ: 0.75-0.83 18 and 25 (m, 1 H), 0.87 (t, J = 7.5 Hz, 2 H), 1.36-1.56 (m, 2 H), 1.97 (t, J = 7.0 Hz, 1 H), 2.06 (t, J = 7.0 Hz, 1 H), 2.18 (td, J= 7.5, 5.5 Hz, 2 H), 2.89-3.02 (m, 2 H), 3.02-3.13 (m, 2 H), 3.28 (s, 1 H), 3.31-3.36 (m, 1 H), 3.43-3.49 (m, 1 H), 3.57 (s, 1 H) 20 Route 5 and methyl 2-oxo-6- ¹H NMR: (400 MHz, intermediates azaspiro[3.4]octane-6- CD₃OD) δ: 2.06-2.15 (m, 2 18 and 26 carboxylate H), 2.94-3.04 (m, 2 H), 3.05-3.17 (m, 2 H), 3.47 (td, J = 6.8, 2.5 Hz, 2 H), 3.54 (d, J = 2.5 Hz, 2 H), 3.69 (s, 3 H) 21 Route 5 and ethyl 2-oxo-6- ¹H NMR: (400 MHz, CDCl₃) intermediates azaspiro[3.4]octane-6- δ: 1.27 (t, J = 7.0 Hz, 3H), 18 and 27 carboxylate 2.08 (t, J = 6.2 Hz, 2H), 2.94-3.17 (m, 4H), 3.49- 3.59 (m, 4H), 4.15 (q, J = 7.0 Hz, 2H) 22 Route 5 and 2-fluoroethyl 2-oxo-6- LCMS (Method F): m/z 216 intermediates azaspiro[3.4]octane-6- (M + H) + (ES+) at 1.79 min, 18 and 28 carboxylate UV inactive 23 Route 5 and 4-nitrophenyl 2-oxo-6- ¹H NMR: (400 MHz, intermediates azaspiro[3.4]octane-6- DMSO-d₆) δ: 2.10 (dt, J = 18 and 29 carboxylate 13.5, 7.0 Hz, 2 H), 2.93- 3.09 (m, 2 H), 3.11-3.24 (m, 2 H), 3.45 (t, J = 7.0 Hz, 1 H), 3.57 (s, 1 H), 3.62 (t, J = 7.0 Hz, 1 H), 3.73 (s, 1 H), 7.40-7.46 (m, 2 H), 8.23-8.29 (m, 2 H) 24 Route a and 4-nitrophenyl 2-(2-oxo-1-oxa- LCMS (Method D): m/z 431 intermediates 3,8-diazaspiro[4.5]dec-8-yl)-6- (M + H)⁺ (ES⁺), at 1.80 min, 7 and 23 azaspiro[3.4]octane-6- UV active carboxylate 25 n-butyryl chloride Commercially available, CAS: 141-75-3 26 methyl chloroformate Commercially available, CAS: 79-22-1 27 ethyl chloroformate Commercially available, CAS: 541-41-3 28 2-fluoroethyl chloroformate Commercially available, CAS: 462-27-1 29 4-nitrophenylchloroformate Commercially available, CAS: 7693-46-1 30 nitromethane Commercially available, CAS: 75-52-5 31 nitroethane Commercially available, CAS: 79-24-3 32 1-nitropropane Commercially available, CAS: 108-03-2 33 1-nitrobutane Commercially available, CAS: 627-05-4 34 2-phenyl-1-nitroethane Commercially available, CAS: 6125-24-2 35 2-bromopropanoic acid ethyl Commercially available, ester CAS: 535-11-5 36 2-bromobutanoic acid ethyl Commercially available, ester CAS: 533-68-6 37 2-bromo-3-methylbutyric acid Commercially available, ethyl ester CAS: 609-12-1 38 2-bromo-2-methylpropionic Commercially available, acid ethyl ester CAS: 600-00-0 39 acetaldehyde Commercially available, CAS: 75-07-0 40 benzaldehyde Commercially available, CAS: 100-52-7 41 methyl-d3 alcohol-d Commercially available, CAS: 811-98-3 42 tert-butyl 6-oxo-2- Commercially available, azaspiro[3.3]heptane-2- CAS: 1181816-12-5 carboxylate 43 tert-butyl 6-oxo-2- Commercially available, azaspiro[3.4]octane-2- CAS: 1363382-39-1 carboxylate 44 Route 5 and ethyl 6-oxo-2- NMR ¹H NMR (400 MHz, intermediates azaspiro[3.3]heptane-2- CDCl₃) 1.26 (t, J = 6.6 Hz, 42 and 27 carboxylate 3H), 3.31 (s, 4H), 4.06- 4.24 (m, 6H) 45 Route 5 and ethyl 6-oxo-2- NMR ¹H NMR (400 MHz, intermediates azaspiro[3.4]octane-2- MeOD-d₄) δ: 1.24 (q, J = 43 and 27 carboxylate 7.0 Hz, 3H), 2.16-2.32 (m, 4H), 2.47 (s, 2H), 3.85- 3.97 (m, 4H), 4.08 (q, J = 7.0 Hz, 2H) 46 ethyl iodide Commercially available, CAS: 75-03-6 47 pyridine-2-carboxaldehyde Commerically available CAS: 1121-60-4 48 Route 6 and 4-(pyridin-2-ylmethyl)-1-oxa- LCMS (Method L): m/z 248 Intermediate 3,8-diazaspiro[4.5]decan-2- (M + H)⁺ (ES⁺) at 5.23 min 47 one UV active 49 Route b and methyl 2-(4-ethyl-2-oxo-1-oxa- LCMS (Method I): m/z 366 Intermediates 3,8-diazaspiro[4.5]dec-8-yl)- (M + H)⁺ (ES⁺) at 3.08 and 9 and 20 2,6-diazaspiro[3.4]octane-6- 3.13 min UV inactive carboxylate 50 propan-2-yl 2-oxo-6- LCMS (Method K): m/z 212 azaspiro[3.4]octane-6- (M + H)⁺ (ES⁺) at 13.90 min carboxylate UV inactive 51 1-bromopropane Commercially available CAS: 106-94-5 52 2-iodopropane Commercially available CAS: 75-30-9 53 1-bromo-2-methyl propane Commercially available CAS: 78-77-3 54 cyclopropyl methyl bromide Commerically available CAS: 7051-34-5 55 ethyl 2-bromo-2- Commercially available, cyclopropylacetate CAS: 1200828-74-5 56 Route 3 and 4-cyclopropyl-1-oxa-3,8- LCMS (Method I): m/z 197 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺) at 2.16 min 15 and 55 UV inactive 57 ethyl 2-cyclobutylacetate Commercially available, CAS: 38353-27-4 58 Route 9 and 4-cyclobutyl-1-oxa-3,8- LCMS (Method F): m/z 211 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺) at 0.71 min 15 and 57 UV inactive 59 ethyl 4,4,4-trifluorobutanoate Commercially available, CAS: 317-26-6 60 Route 7 and 4-(2,2,2-trifluoroethyl)-1-oxa- LCMS (Method H): m/z 239 intermediates 3,8-diazaspiro[4.5]decan-2- (M + H)⁺ (ES⁺) at 2.79 min 15 and 59 one UV inactive 61 ethyl 3-phenylpropionate Commercially available, CAS: 2021-28-5 62 Route 9 and 4-benzyl-1-oxa-3,8- LCMS (Method H): m/z 247 intermediates diazaspiro[4.5]decan-2-one (M + H)⁺ (ES⁺) at 3.41 min 15 and 61 UV inactive 63 methyl iodide Commercially available, CAS: 74-88-4 64 ethyl cyclobutanecarboxylate Commercially available, CAS: 14924-53-9 65 Route 7 and 11-oxa-8,13- LCMS (Method G): m/z 197 intermediates diazadispiro[3.0.5.3]tridecan- (M + H)⁺ (ES⁺) at 3.40 min 15 and 64 12-one UV inactive 66 methyl 3,3- Commercially available, difluorocyclobutane-1- CAS: 1234616-13-7 carboxylate 67 Route 7 and 2,2-difluoro-11-oxa-8,13- LCMS (Method H): m/z 233 intermediates diazadispiro[3.0.5.3]tridecan- (M + H)⁺ (ES⁺) at 2.76 min 15 and 64 12-one UV inactive 68 methyl cyclopentane Commercially available, carboxylate CAS: 4630-80-2 69 Route 7 and 12-oxa-9,14- LCMS (Method F): m/z 211 intermediates diazadispiro[4.0.5.3]tetradecan- (M + H)⁺ (ES⁺) at 0.49 min 15 and 65 13-one UV inactive 70 methyl-d₃ iodide Commercially available, CAS: 865-50-9 71 1-bromo-2-methoxyz ethane Commercially available CAS: 6482-24-2 72 2-chloroacetonitrile Commercially available CAS: 107-14-2 73 2,2,2-trifluoroethyl Commercially available trifluoromethanesulfonate CAS: 6226-25-1 74 tert-butyl pyrrolidine-1- Commercially available carboxylate CAS: 86953-79-9 75 benzyl-4-oxopiperidine-1- Commercially available carboxylate CAS: 19099-93-5 76 Route 8 and tetrahydrospiro[piperidine-4,1′- LCMS (Method F): m/z 197 intermediates pyrrolo[1,2-c][1,3]oxazol]-3′- (M + H)⁺ (ES⁺) at 1.99 min 74 and 75 one UV inactive 77 propionaldehyde Commercially available CAS: 123-38-6 78 Route 4 and 1-propyl-1,2,8- LCMS (Method K): m/z 198 intermediates triazaspiro[4.5]decan-3-one. (M + H)⁺ (ES⁺), at 2.55 min, 16 and 77 HCl UV inactive 79 acetone Commercially available CAS: 67-64-1 80 1-(propan-2-yl)-1,2,8- LCMS (Method G): m/z 198 triazaspiro[4.5]decan-3- (M + H)⁺ (ES⁺), at 3.23 min, one.HCl UV inactive 81 propyl(triphenyl)phosphonium Commercially available bromide CAS: 6228-47-3 82 cyclopropanamine Commercially available CAS: 765-30-0 83 Route 10 and 3-cyclopropyl-4-ethyl-1-oxa- m/z 225 (M + H)⁺ (ES⁺) intermediates 3,8-diazaspiro[4.5]decan-2- 16 and 82 one 84 methoxylamine hydrochloride Commercially available CAS: 593-56-6 85 Route 10 and 4-ethyl-3-methoxy-1-oxa-3,8- m/z 215 (M + H)⁺ (ES⁺) intermediates diazaspiro[4.5]decan-2-one 16 and 84 86 Route 4 tert-butyl 1-ethyl-3-oxo-1,2,8- LCMS (Method G): m/z 284 intermediate triazaspiro[4.5]decane-8- (M + H)⁺ (ES⁺), at 4.69 min, 16 carboxylate UV inactive 87 Route 11 1-ethyl-2-(methyl-d3)-1,2,8- LCMS (Method I): m/z 202 intermediate triazaspiro[4.5]decan-3-one (M + H)⁺ (ES⁺), at 2.12 min, 70 and 86 UV inactive

TABLE 3 Syn- Ex. Inter- thetic LCMS LCMS No. Name mediate method ¹H NMR Method data 1-1 ethyl 6-(3-oxo-2,8- 44 and 1 a (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), 1.46-1.53 B m/z 322 diazaspiro[4.5]dec-8-yl)-2- (m, 4 H), 1.84-1.92 (m, 2 H), 1.97 (s, 2 H), 2.00-2.25 (M + H)⁺ azaspiro[3.3]heptane-2- (m, 6 H), 2.71-2.75 (m, 1 H), 2.98 (s, 2 H), 3.72-3.78 (ES+), at carboxylate (m, 2 H), 3.86-3.90 (m, 2 H), 3.96 (q, J = 7.0 Hz, 2 H), 2.10 min, 7.46 (s, 1 H) UV inactive 2-1 Isomer 1: ethyl 6-(4-ethyl- 44 and 9 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.0 Hz, 3 H), 1.14 (t, I m/z 352 2-oxo-1-oxa-3,8- J = 7.0 Hz, 3 H), 1.22-1.30 (m, 2 H), 1.42-1.52 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- 1.54-1.76 (m, 3 H), 1.85-2.02 (m, 3 H), 2.20-2.32 (m, (ES+), at azaspiro[3.3]heptane-2- 2 H), 2.54-2.62 (m, 2 H), 2.90-2.96 (m, 1 H), 3.17-3.25 3.29 min, carboxylate (m, 1 H), 3.74-3.80 (m, 2 H), 3.88-3.94 (m, 2 H), UV inactive 3.97 (q, J = 7.0 Hz, 2 H), 7.82 (s, 1 H) 2-1 Isomer 2: ethyl 6-(4-ethyl- 44 and 9 b 400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.0 Hz, 3 H), 1.14 (t, I m/z 352 2-oxo-1-oxa-3,8- J = 7.0 Hz, 3 H), 1.22-1.30 (m, 2 H), 1.42-1.52 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- 1.54-1.76 (m, 3 H), 1.85-2.00 (m, 3 H), 2.20-2.31 (m, (ES+), at azaspiro[3.3]heptane-2- 2 H), 2.54-2.62 (m, 2 H), 2.90-2.95 (m, 1 H), 3.19-3.25 3.25 min, carboxylate (m, 1 H), 3.74-3.80 (m, 2 H), 3.88-3.94 (m, 2 H), UV inactive 3.97 (q, J = 7.0 Hz, 2 H), 7.82 (s, 1 H) 2-2 Racemic: ethyl 6-(3,4- 46 and e 400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3 H), 1.03 (t, I m/z 380 diethyl-2-oxo-1-oxa-3,8- Example J = 7.0 Hz, 3 H), 1.14 (t, J = 7.0 Hz, 3 H), 1.47-1.78 (m, 6 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- 2-1 H), 1.85-2.02 (m, 4 H), 2.23-2.29 (m, 2 H), 2.56-2.63 (ES+), at azaspiro[3.3]heptane-2- (m, 4 H), 2.92-3.04 (m, 1 H), 3.28-3.31 (m, 1 H), 3.74-3.80 3.74 min, carboxylate (m, 2 H), 3.88-3.94 (m, 2 H), 3.97 (q, J = 7.0 Hz, 2 H) UV inactive 2-3 ethyl 6-(4,4-dimethyl-2-oxo- 44 and 11 b 400 MHz, DMSO-d₆) δ: 1.08 (s, 6 H), 1.14 (t, J = 7.0 Hz, I m/z 352 1-oxa-3,8- 3 H), 1.51-1.59 (m, 2 H), 1.67-1.74 (m, 2 H), 1.82-1.95 (M + H)⁺ diazaspiro[4.5]decan-8-yl)- (m, 4 H), 2.23-2.30 (m, 2 H), 2.56-2.61 (m, 1 H), 2.64-2.69 (ES+), at 2-azaspiro[3.3]heptane-2- (m, 2 H), 3.75-3.79 (m, 2 H), 3.88-3.93 (m, 2 H), 3.20 min, carboxylate 3.97 (q, J = 7.0 Hz, 2 H), 7.52 (s, 1 H) UV inactive 2-4 ethyl 6-(3-ethyl-4,4- 46 and c 400 MHz, DMSO-d₆) δ: 1.06 (t, J = 7.0 Hz, 3 H), 1.09 (s, I m/z 380 dimethyl-2-oxo-1-oxa-3,8- Example 6 H), 1.14(t, J = 7.0 Hz, 3 H), 1.51-1.70 (m, 4 H), 1.82-1.95 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- 2-3 (m, 4 H), 2.23-2.30 (m, 2 H), 2.56-2.61 (m, 1 H), (ES+), at azaspiro[3.3]heptane-2- 2.64-2.70 (m, 2 H), 3.06 (q, J = 7.0 Hz, 2 H), 3.74-3.80 3.59 min, carboxylate (m, 2 H), 3.88-3.93 (m, 2 H), 3.97 (q, J = 7.0 Hz, 2 H) UV inactive 2-5 Racemic: ethyl 6-(3′- 44 and 76 b (400 MHz, DMSO-d₆) δ: 1.15 (t, J = 7.2 Hz, 3 H), 1.38-1.48 I m/z 364 oxotetrahydro-1H- (m, 1 H), 1.69-1.89 (m, 6 H), 1.89-2.06 (m, 4 H), (M + H)⁺ spiro[piperidine-4,1′- 2.07-2.22 (m, 2 H), 2.23-2.32 (m, 2 H), 2.32-2.49 (m, 2 H), (ES+), at pyrrolo[1,2-c][1,3]oxazol]-1- 3.04-3.13 (m, 1 H), 3.30-3.43 (m, 1 H), 3.50-3.58 3.40 min, yl)-2-azaspiro[3.3]heptane- (m, 1 H), 3.75-3.86 (m, 2 H), 3.88-3.95 (m, 2 H), 3.96-4.04 UV inactive 2-carboxylate (q, J = 7.0 Hz, 2 H) 3-1 Isomer 2: methyl 2-(3-oxo- 1 and 20 a (400 MHz, DMSO-d₆) δ: 1.49 (t, J = 5.0 Hz, 4 H), 1.73 (t, E m/z 322 2,8-diazaspiro[4.5]dec-8- J = 8.20 Hz, 2 H), 1.81 (dt, J = 13.5, 6.5 Hz, 2 H), 1.91-2.00 (M + H)⁺ yl)-6-azaspiro[3.4]octane-6- (m, 4 H), 2.00-2.31 (m, 4 H), 2.56-2.73 (m, 1 H), (ES+), at carboxylate 2.97 (s, 2 H), 3.12 (d, J = 3.0 Hz, 2 H), 3.25 (q, J = 6.5 Hz, 2.38 min, 2 H), 3.53 (s, 3 H), 7.48 (s, 1 H) UV inactive 3-2 Isomer 2: ethyl 2-(3-oxo- 1 and 21 a (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.49 (t, E m/z 336 2,8-diazaspiro[4.5]dec-8- J = 5.5 Hz, 4 H), 1.72 (t, J = 10.0 Hz, 2 H), 1.76-1.87 (m, 2 H), (M + H)⁺ yl)-6-azaspiro[3.4]octane-6- 1.90-1.98 (m, 4 H), 1.98-2.15 (m, 2 H), 1.98-2.29 (ES+), at carboxylate (m, 2 H), 2.55-2.69 (m, 1 H), 2.97 (s, 2 H), 3.12 (d, J = 2.75 min, 6.0 Hz, 2 H), 3.25 (q, J = 6.5 Hz, 2 H), 3.97 (q, J = 7.0 Hz, UV inactive 2 H), 7.47 (s, 1 H) 3-3 Isomer 2: ethyl 2-(1-methyl- 2 and 21 b (400 MHz, DMSO-d₆) δ: 0.98 (d, J = 6.5 Hz, 3 H), 1.16 (t, F m/z 350 3-oxo-2,8- J = 7.0 Hz, 3 H), 1.31-1.57 (m, 5 H), 1.69-1.78 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.78-2.02 (m, 7 H), 2.03-2.14 (m, 1 H), 2.60-2.70 (m, (ES+), at azaspiro[3.4]octane-6- 2 H), 3.09-3.30 (m, 5 H), 4.00 (q, J = 7.0 Hz, 2 H), 7.59 1.54 min, carboxylate (s, 1 H) UV inactive 3-4 Isomer 1: methyl 2-(1-ethyl- 3 and 20 c (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.14-1.24 I m/z 350 3-oxo-2,8- (m, 2 H), 1.35-1.54 (m, 5 H), 1.70-2.11 (m, 10 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2.61-2.66 (m, 1 H), 2.96-2.98 (m, 1 H), 3.20-3.26 (m, 4 H), (ES+), at azaspiro[3.4]octane-6- 3.41-3.51 (m, 1 H), 3.57 (s, 3 H), 7.87 (s, 1 H) 3.05 min, carboxylate UV inactive 3-4 Isomer 2: methyl 2-(1-ethyl- 3 and 20 c (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.14-1.24 I m/z 350 3-oxo-2,8- (m, 2 H), 1.35-1.54 (m, 5 H), 1.70-2.11 (m, 10 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2.61-2.66 (m, 1 H), 2.96-2.98 (m, 1 H), 3.20-3.26 (m, 4 (ES+), at azaspiro[3.4]octane-6- H), 3.34 (s, 3 H), 3.41-3.51 (m, 1H), 7.87 (s, 1 H) 3.09 min, carboxylate UV inactive 3-4 Isomer 3: methyl 2-(1-ethyl- 3 and 20 c (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.16-1.24 I m/z 350 3-oxo-2,8- (m, 2 H), 1.35-1.55 (m, 5 H), 1.72-2.11 (m, 10H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2.60-2.68 (m, 1 H), 2.96-2.98 (m, 1 H), 3.14-3.17 (m, 2 H), (ES+), at azaspiro[3.4]octane-6- 3.26-3.30 (m, 2 H), 3.41-3.51 (m, 1 H), 3.55 (s, 3 H), 3.15 min, carboxylate 7.86 (s, 1 H) UV inactive 3-4 Isomer 4: methyl 2-(1-ethyl- 3 and 20 c (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.14-1.24 I m/z 350 3-oxo-2,8- (m, 2 H), 1.35-1.52 (m, 5 H), 1.72-2.11 (m, 10 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2.60-2.68 (m, 1 H), 2.96-2.98 (m, 1 H), 3.14-3.17 (m, 2 (ES+), at azaspiro[3.4]octane-6- H), 3.22-3.30 (m, 2 H), 3.41-3.49 (m, 1 H), 3.56 (s, 3 H), 3.16 min, carboxylate 7.86 (s, 1 H) UV inactive 3-5 Isomer 2: ethyl 2-(1-ethyl- 3 and 21 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.0 Hz, 3 H), 1.16 (t, F m/z 364 3-oxo-2,8- J = 7.0 Hz, 3 H), 1.21-1.28 (m, 2 H), 1.31-1.57 (m, 5 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.69-1.78 (m, 2 H), 1.78-2.02 (m, 7 H), 2.03-2.13 (m, 1 (ES+), at azaspiro[3.4]octane-6- H), 2.59-2.70 (m, 2 H), 2.97 (d, J = 8.0 Hz, 1 H), 3.14 (d, 1.59 min, carboxylate J = 6.0 Hz, 2 H), 3.27 (q, J = 7.0 Hz, 2 H), 4.00 (q, J = 7.0 UV inactive Hz, 2 H), 7.86 (s, 1 H) 3-6 Isomer 2: ethyl 2-(3-oxo-1- 4 and 21 b (400 MHz, DMSO-d₆) δ: 0.88 (t, J = 6.5 Hz, 3 H), 1.08-1.24 F m/z 378 propyl-2,8- (m, 5 H), 1.29-1.57 (m, 7 H), 1.68-1.78 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.78-2.02 (m, 7 H), 2.04-2.14 (m, 1 H), 2.57-2.69 (m, 2 (ES+), at azaspiro[3.4]octane-6- H), 3.06 (d, J = 8.0 Hz, 1 H), 3.14 (d, J = 6.0 Hz, 2 H), 1.68 min, carboxylate 3.22-3.30 (m, 2 H), 3.99 (q, J = 7.0 Hz, 2 H), 7.85 (s, 1 H) UV inactive 3-7 Isomer 2: methyl 2-(1- 5 and 20 b (400 MHz, DMSO-d₆): 1.39-1.67 (m, 4H), 1.69-2.03 F m/z 412 benzyl-3-oxo-2,8- (m, 9H), 2.12-2.24 (m, 1H), 2.46-2.71 (m, 4H), 2.83 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (dd, J = 13.7, 4.3 Hz, 1H), 3.15 (d, J = 2.7 Hz, 2H), 3.24-3.37 (ES+), at azaspiro[3.4]octane-6- (m, 2H), 3.42 (dd, J = 9.8, 4.3 Hz, 1H), 3.56 (s, 3H), 1.71 min, carboxylate 7.16-7.26 (m, 3H), 7.26-7.35 (m, 2H), 7.42 (s, 1H) UV active 3-8 Isomer 2: ethyl 2-(1-benzyl- 5 and 21 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.40-1.66 F m/z 426 3-oxo-2,8- (m, 5 H), 1.69-1.79 (m, 2 H), 1.79-2.03 (m, 7 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2.14-2.21 (m, 1 H), 2.59-2.71 (m, 2 H), 2.83 (dd, J = (ES+), at azaspiro[3.4]octane-6- 13.5, 4.0 Hz, 1 H), 3.14 (d, J = 5.5 Hz, 2 H), 3.20-3.30 1.72 min, carboxylate (m, 3 H), 3.41-3.48 (m, 1 H), 4.00 (q, J = 7.0 Hz, 2 H), UV active 7.16-7.26 (m, 3 H), 7.26-7.34 (m, 2 H), 7.43 (s, 1 H) 3-9 Isomer 2: ethyl 2-(6-fluoro- 6 and 21 a (400 MHz, DMSO-d₆) δ: 1.08-1.24 (m, 3 H), 1.41-1.62 E m/z 354 3-oxo-2,8- (m, 1 H), 1.68-1.91 (m, 5 H), 1.92-1.99 (m, 2 H), 2.02 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (s, 1 H), 2.05-2.17 (m, 2 H), 2.20-2.37 (m, 2 H), 2.52-2.61 (ES+), at azaspiro[3.4]octane-6- (m, 1 H), 2.61-2.78 (m, 2 H), 2.91 (d, J = 10.0 Hz, 1 H), 0.13 min, carboxylate 3.13 (d, J = 6.5 Hz, 1 H), 3.15-3.27 (m, 3 H), 3.89-4.18 UV inactive (m, 2 H), 4.35-4.47 (m, 0.5 H), 4.47-4.59 (m, 0.5 H), 7.59 (s, 1 H) 4-1 Isomer 2: methyl 2-(2-oxo- 7 and 20 a (400 MHz, DMSO-d₆) δ: 1.59-1.88 (m, 8 H), 1.97 (ddd, E m/z 324 1-oxa-3,8- J = 9.0, 7.0, 3.0 Hz, 2 H), 2.20-2.30 (m, 3 H), 2.58-2.76 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (m, 2 H), 3.13 (d, J = 4.0 Hz, 2 H), 3.18 (s, 2 H), 3.22-3.29 (ES+), at azaspiro[3.4]octane-6- (m, 2 H), 3.53 (s, 3 H), 7.45 (s, 1 H) 2.05 min, carboxylate UV inactive 4-2 Isomer 2: (²H₃)methyl 2-(2- 24 and 41 d (400 MHz, DMSO-d₆) δ: 1.62-1.86 (m, 8 H), 1.97 (ddd, E m/z 327 oxo-1-oxa-3,8- J = 9.0, 7.0, 2.5 Hz, 2 H), 2.09-2.38 (m, 3 H), 2.60-2.74 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (m, 1 H), 3.13 (d, J = 3.5 Hz, 2 H), 3.18 (s, 2 H), 3.21-3.29 (ES+), at azaspiro[3.4]octane-6- (m, 3 H), 7.44 (s, 1 H) 2.14 min, carboxylate UV inactive 4-3 Isomer 1: ethyl 2-(2-oxo-1- 7 and 21 a (400 MHz, DMSO-d₆) δ: 1.15 (t, J = 7.5 Hz, 3 H), 1.56-1.86 B m/z 338 oxa-3,8-diazaspiro[4.5]dec- (m, 8 H), 1.90-2.06 (m, 2 H), 2.09-2.39 (m, 4 H), (M + H)⁺ 8-yl)-6-azaspiro[3.4]octane- 2.60-2.75 (m, 1 H), 3.14-3.26 (m, 6 H), 3.99 (q, J = 7.0 Hz, (ES+), at 6-carboxylate 2 H), 7.43 (s, 1 H) 2.25 min, UV inactive 4-3 Isomer 2: ethyl 2-(2-oxo-1- 7 and 21 a (400 MHz, DMSO-d₆) δ: 1.09-1.19 (m, 3 H), 1.59-1.87 B m/z 338 oxa-3,8-diazaspiro[4.5]dec- (m, 8 H), 1.97 (ddd, J = 9.0, 7.0, 2.0 Hz, 2 H), 2.13-2.37 (M + H)⁺ 8-yl)-6-azaspiro[3.4]octane- (m, 4 H), 2.61-2.76 (m, 1 H), 3.13 (d, J = 6.0 Hz, 2 H), (ES+), at 6-carboxylate 3.18 (s, 2 H), 3.23-3.27 (m, 2 H), 3.97 (q, J = 7.0 Hz, 2 2.38 min, H), 7.43 (s, 1 H) UV inactive 4-4 Isomer 2: propan-2-yl 2-(2- 7 and 50 a (400 MHz, CDCl₃) δ: 1.20-1.30 (m, 7 H), 1.74-2.12 (m, I m/z 350 oxo-1-oxa-3,8- 10 H), 2.23-2.65 (m, 3 H), 2.68-2.78 (m, 1 H), 3.25-3.45 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (m, 6 H), 4.88-4.95 (m, 2 H) (ES+), at azaspiro[3.4]octane-6- 3.49 min, carboxylate UV inactive 4-5 Mixture of diastereomers: 7 and 22 a (400 MHz, DMSO-d₆) δ: 1.59-1.89 (m, 8 H), 1.92-2.10 E m/z 356 2-fluoroethyl 2-(2-oxo-1- (m, 2 H), 2.11-2.42 (m, 4 H), 2.57-2.77 (m, 1 H), 3.09-3.30 (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- (m, 6 H), 4.01-4.29 (m, 2 H), 4.50 (d, J = 3.10 Hz, 1 (ES+), at 8-yl)-6-azaspiro[3.4]octane- H), 4.62 (d, J = 3.0 Hz, 1 H), 7.44 (s, 1 H) 2.05 min and 6-carboxylate 2.20 min, UV inactive 4-6 Mixture of diastereomers: 7 and 19 a (400 MHz, DMSO-d₆) δ: 0.81-0.93 (m, 3 H), 1.39-1.55 E m/z 336 8-(6-butanoyl-6- (m, 2 H), 1.59-1.83 (m, 8 H), 1.88 (t, J = 6.5 Hz, 1 H), (M + H)⁺ azaspiro[3.4]oct-2-yl)-1- 1.92-2.06 (m, 2 H), 2.07-2.37 (m, 6 H), 2.60-2.77 (m, 1 H), (ES+), at oxa-3,8- 3.16-3.24 (m, 2 H), 3.24-3.29 (m, 2 H), 3.35-3.43 1.97 min and diazaspiro[4.5]decan-2-one (m, 1 H), 7.45 (s, 1 H) 2.17 min, UV inactive 4-7 Isomer 2: ethyl 2-(2-oxo-3- 51 and e (400 MHz, DMSO-d₆) δ: 0.83 (t, J = 7.3 Hz, 3H), 1.09-1.25 I m/z 380 propyl-1-oxa-3,8- Example (m, 3H), 1.41-1.53 (m, 2H), 1.63-1.83 (m, 7H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-3 1.98-2.19 (m, 2H), 2.19-2.41 (m, 3H), 3.10 (t, J = 7.0 (ES+), at azaspiro[3.4]octane-6- Hz, 2H), 3.14-3.31 (m, 8H), 4.01 (q, J = 7.0 Hz, 2H), 4.12 3.79 min, carboxylate (q, J = 5.2 Hz, 1H) UV inactive 4-8 Isomer 2: ethyl 2-[2-oxo-3- 52 and e (400 MHz, DMSO-d₆) δ: 1.09 (d, J = 7.0 Hz, 6 H), 1.16 (t, I m/z 380 (propan-2-yl)-1-oxa-3,8- Example J = 7.0 Hz, 3 H), 1.69-1.87 (m, 8 H), 1.97-2.01 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl]-6- 4-3 2.12-2.40 (m, 3 H), 2.56-2.73 (m, 2 H), 3.15 (d, J = 6.5 (ES+), at azaspiro[3.4]octane-6- Hz, 2 H), 3.22 (s, 2 H), 3.28 (q, J = 7.0 Hz, 2 H), 3.87 3.80 min, carboxylate (quint, J = 7.0 Hz, 1 H), 4.00 (q, J = 7.0 Hz, 2 H) UV inactive 4-9 Isomer 2: ethyl 2-[3-(2- 53 and e (400 MHz, DMSO-d₆) δ: 0.84 (d, J = 6.5 Hz, 6 H), 1.16 (t, I m/z 394 methylpropyl)-2-oxo-1-oxa- Example J = 7.0 Hz, 3 H), 1.75-2.03 (m, 12 H), 2.19-2.42 (m, 3 H), (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-3 2.94 (d, J = 7.5 Hz, 2 H), 3.15-3.18 (m, 3 H), 3.25-3.29 (ES+), at yl]-6-azaspiro[3.4]octane-6- (m, 4 H), 4.00 (q, J = 7.0 Hz, 2 H) 4.07 min, carboxylate UV inactive 4-10 Isomer 2: ethyl 2-[3- 54 and e (400 MHz, DMSO-d₆) δ: 0.16-0.19 (m, 2 H), 0.45-0.49 I m/z 392 (cyclopropylmethyl)-2-oxo- Example (m, 2 H), 0.85-0.95 (m, 1 H), 1.16 (t, J = 7.0 Hz, 3 H), (M + H)⁺ 1-oxa-3,8- 4-3 1.68-1.87 (m, 8 H), 1.97-2.02 (m, 2 H), 2.09-2.41 (m, 3 H), (ES+), at diazaspiro[4.5]dec-8-yl]-6- 2.64-2.73 (m, 1 H), 3.00 (d, J = 7.0 Hz, 2 H), 3.14-3.16 3.92 min, azaspiro[3.4]octane-6- (m, 3 H), 3.27 (q, J = 6.5 Hz, 2 H), 3.37 (s, 2 H), 3.99 UV inactive carboxylate (q, J = 7.0 Hz, 2 H) 4-11 Isomer 2 (racemic): ethyl 2- 8 and 21 b (400 MHz, DMSO-d₆) δ: 1.03 (d, J = 6.5 Hz, 3 H), 1.16 (t, F m/z 352 (4-methyl-2-oxo-1-oxa-3,8- J = 7.0 Hz, 3 H), 1.52-1.80 (m, 6 H), 1.80-1.90 (m, 2 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.98-2.02 (m, 4 H), 2.51-2.60 (m, 2 H), 2.66-2.74 (m, (ES+), at azaspiro[3.4]octane-6- 1 H), 3.15 (d, J = 5.59 Hz, 2 H), 3.21-3.30 (m, 2 H), 3.47 1.59 min, carboxylate (d, J = 6.5 Hz, 1 H), 4.00 (q, J = 7.0 Hz, 2 H), 7.55 (s, 1 H) UV inactive 4-12 Isomer 1: ethyl 2-(4-ethyl- 9 and 21 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.14-1.19 F m/z 366 2-oxo-1-oxa-3,8- (m, 3 H), 1.22-1.35 (m, 1 H), 1.43-1.55 (m, 1 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.58-1.83 (m, 8 H), 1.88-2.07 (m, 4 H), 2.56-2.63 (m, (ES+), at azaspiro[3.4]octane-6- 2 H), 2.65-2.76 (m, 1 H), 3.15-3.29 (m, 5 H), 4.01 (q, 1.64 min, carboxylate J = 7.0 Hz, 2 H), 7.80 (s, 1 H) UV inactive 4-12 Isomer 2: ethyl 2-(4-ethyl- 9 and 21 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.09-1.22 F m/z 366 2-oxo-1-oxa-3,8- (m, 3 H), 1.23-1.36 (m, 1 H), 1.44-1.54 (m, 1 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.55-1.84 (m, 8 H), 1.89-2.06 (m, 4 H), 2.56-2.62 (m, (ES+), at azaspiro[3.4]octane-6- 2 H), 2.66-2.75 (m, 1 H), 3.14-3.30 (m, 5 H), 4.01 (q, 1.64 min, carboxylate J = 7.0 Hz, 2 H), 7.80 (br. s., 1 H) UV inactive 4-12 Isomer 3: ethyl 2-(4-ethyl- 9 and 21 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.16 (t, F m/z 366 2-oxo-1-oxa-3,8- J = 7.0 Hz, 3 H), 1.21-1.35 (m, 1 H), 1.41-1.55 (m, 1 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.55-1.90 (m, 8 H), 1.90-2.06 (m, 4 H), 2.56-2.63 (m, (ES+), at azaspiro[3.4]octane-6- 2 H), 2.66-2.76 (m, 1 H), 3.15 (d, J = 6.0 Hz, 2 H), 3.19-3.31 1.67 min, carboxylate (m, 3 H), 4.00 (q, J = 7.0 Hz, 2 H), 7.81 (s, 1 H) UV inactive 4-12 Isomer 4: ethyl 2-(4-ethyl- 9 and 21 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.16 (t, F m/z 366 2-oxo-1-oxa-3,8- J = 7.0 Hz, 3 H), 1.21-1.33 (m, 1 H), 1.43-1.54 (m, 1 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1.56-1.89 (m, 8 H), 1.91-2.05 (m, 4 H), 2.56-2.63 (m, (ES+), at azaspiro[3.4]octane-6- 2 H), 2.66-2.73 (m, 1 H),3.15 (d, J = 6.0 Hz, 2 H), 3.19-3.31 1.67 min, carboxylate (m, 3 H), 4.00 (q, J = 7.0 Hz, 2 H), 7.80 (s, 1 H) UV inactive 4-13 Isomer 2 (racemic): ethyl 2- 10 and 21 b (400 MHz, DMSO-d₆) δ: 0.79-0.95 (m, 6H), 1.17 (t, J = F m/z 380 [2-oxo-4-(propan-2-yl)-1- 7.0 Hz, 3H), 1.62-1.84 (m, 9H), 1.90-2.11 (m, 4H), 2.54-2.77 (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- (m, 3H), 3.10 (d, J = 6.0 Hz, 1H), 3.19-3.31 (m, (ES+), at 8-yl]-6-azaspiro[3.4]octane- 4H), 4.01 (q, J = 7.0 Hz, 2H), 7.71 (s, 1H) 1.65 min, 6-carboxylate UV active 4-14 Isomer 2 (racemic): ethyl 2- 56 and 21 b (400 MHz, DMSO-d₆) δ: 0.10-0.18 (m, 1 H), 0.22-0.29 F m/z 380 (4-cyclopropyl-2-oxo-1-oxa- (m, 1 H), 0.42-0.51 (m, 2 H), 0.81-0.89 (m, 1 H), 1.16 (t, (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- J = 7.0 Hz, 3 H), 1.60-2.02 (m, 12 H), 2.55-2.75 (m, 4 (ES+), at yl)-6-azaspiro[3.4]octane-6- H), 3.15 (d, J = 6.0 Hz, 2 H), 3.28 (q, J = 6.5 Hz, 2 H), 1.52 min, carboxylate 4.00 (q, J = 7.0 Hz, 2 H), 7.74 (s, 1 H) UV active 4-15 Isomer 1 (racemic): ethyl 2- 58 and 21 b (400 MHz, DMSO-d₆) δ: 1.15-1.19 (m, 3 H), 1.24 (s, 1 H), I m/z 392 (4-cyclobutyl-2-oxo-1-oxa- 1.46-2.03 (m, 19 H), 2.65-2.70 (m, 2 H), 3.18-3.29 (m, (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 5 H), 4.01 (q, J = 7.0 Hz, 2 H), 7.83 (s, 1 H) (ES+), at yl)-6-azaspiro[3.4]octane-6- 3.72 min, carboxylate UV inactive 4-15 Isomer 2 (racemic): ethyl 2- 58 and 21 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.24 (s, I m/z 392 (4-cyclobutyl-2-oxo-1-oxa- 1 H), 1.44-2.01 (m, 19 H), 2.66-2.70 (m, 2 H), 3.14 (d, J = (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 6.0 Hz, 2 H), 3.25-3.31 (m, 3 H), 4.00 (q, J = 7.0 Hz, 2 H), (ES+), at yl)-6-azaspiro[3.4]octane-6- 7.83 (s, 1 H) 3.77 min, carboxylate UV inactive 4-16 Isomer 2 (racemic): methyl 60 and 20 b (400 MHz, DMSO-d₆) δ: 1.60-2.05 (m, 12 H), 2.34-2.45 I m/z 406 2-[2-oxo-4-(2,2,2- (m, 1 H), 2.60-2.73 (m, 4 H), 3.15-3.16 (m, 2 H), 3.26-3.31 (M + H)⁺ trifluoroethyl)-1-oxa-3,8- (m, 2 H), 3.56 (s, 3 H), 3.63-3.66 (m, 1 H), 7.92 (s, 1 H) (ES+), at diazaspiro[4.5]dec-8-yl]-6- 2.87 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-17 Isomer 1 (racemic): ethyl 2- 60 and 21 b (400 MHz, DMSO-d₆) δ: 1.15-1.19 (m, 3 H), 1.66-1.76 I m/z 420 [2-oxo-4-(2,2,2- (m, 9 H), 1.94-2.03 (m, 3 H), 2.62-2.72 (m, 5 H), 3.22-3.28 (M + H)⁺ trifluoroethyl)-1-oxa-3,8- (m, 4 H), 3.63-3.66 (m, 1 H), 4.01 (q, J = 7.0 Hz, 2 H), (ES+), at diazaspiro[4.5]dec-8-yl]-6- 7.93 (s, 1 H) 3.60 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-17 Isomer 2 (racemic): ethyl 2- 60 and 21 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.63-2.09 I m/z 420 [2-oxo-4-(2,2,2- (m, 12 H), 2.66-2.72 (m, 5 H), 3.15 (d, J = 6.0 Hz, 2 H), (M + H)⁺ trifluoroethyl)-1-oxa-3,8- 3.26-3.31 (m, 2H), 3.64-3.66 (m, 1 H), 4.00 (q, J = (ES+), at diazaspiro[4.5]dec-8-yl]-6- 7.0 Hz, 2 H), 7.93 (s, 1 H) 3.67 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-18 Isomer 1 (racemic): ethyl 2- 60 and 21 b (400 MHz, DMSO-d₆) δ: 1.16-1.24 (m, 3 H), 1.52-2.00 I m/z 428 (4-benzyl-2-oxo-1-oxa-3,8- (m, 12 H), 2.59-2.67 (m, 4 H), 2.86 (dd, J = 14.0, 5.5 Hz, (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 1 H), 3.13-3.27 (m, 4 H), 3.72-3.76 (m, 1 H), 4.01 (q, (ES+), at azaspiro[3.4]octane-6- J = 7.0 Hz, 2 H), 7.21-7.34 (m, 5 H), 7.57 (s, 1 H) 3.94 min, carboxylate inactive 4-18 Isomer 2 (racemic): ethyl 2- 60 and 21 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.57-1.98 I m/z 428 (4-benzyl-2-oxo-1-oxa-3,8- (m, 12 H), 2.62-2.68 (m, 4 H), 2.87 (dd, J = 14.0, (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 5.5 Hz, 1 H), 3.14 (d, J = 6.0 Hz, 2 H), 3.25-3.30 (m, 2 (ES+), at azaspiro[3.4]octane-6- H), 3.72-3.76 (m, 1 H), 4.00 (q, J = 7.0 Hz, 2 H), 7.21-7.34 3.98 min, carboxylate (m, 5 H), 7.57 (s, 1 H) inactive 4-19 Isomer 2 (racemic): ethyl 2- 48 and 21 g (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.51-2.04 J m/z 429 [2-oxo-4-(pyridin-2- (m, 15 H), 2.80-2.86 (m, 1 H), 3.03 (dd, J = 14.5, (M + H)⁺ ylmethyl)-1-oxa-3,8- 5.5 Hz, 1 H), 3.13-3.15 (m, 2 H), 3.24-3.28 (m, 2 H), (ES+), at diazaspiro[4.5]dec-8-yl]-6- 3.96-4.02 (m, 3 H), 7.23-7.31 (m, 2 H), 7.53 (br. s, 1 H), 1.89 min, azaspiro[3.4]octane-6- 7.70-7.75 (m, 1 H), 8.50-8.51 (m, 1 H) inactive carboxylate 4-20 Isomer 1: ethyl 2-(4-ethyl- 63 and e (400 MHz, CD₃OD) δ: 1.04 (t, J = 7.5 Hz, 3 H), 1.25-1.29 I m/z 380 3-methyl-2-oxo-1-oxa-3,8- Example (m, 3 H), 1.62-2.06 (m, 12 H), 2.19-2.25 (m, 2 H), 2.32-2.45 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 2 H), 2.85-3.06 (m, 5 H), 3.37-3.42 (m, 4 H), (ES+), at azaspiro[3.4]octane-6- Isomer 1 4.13 (q, J = 7.0 Hz, 2 H) 3.71 min, carboxylate UV inactive 4-20 Isomer 2: ethyl 2-(4-ethyl- 63 and e (400 MHz, CD₃OD) δ: 1.03 (t, J = 7.5 Hz, 3 H), 1.25-1.29 I m/z 380 3-methyl-2-oxo-1-oxa-3,8- Example (m, 3 H), 1.64-1.95 (m, 10 H), 2.16-2.28 (m, 4 H), 2.79-2.89 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 5 H), 3.36-3.41 (m, 4 H), 4.13 (q, J = 7.0 Hz, 2 H), (ES+), at azaspiro[3.4]octane-6- Isomer 2 4.65 (s, 2 H) 3.71 min, carboxylate UV inactive 4-20 Isomer 3: ethyl 2-(4-ethyl- 63 and e (400 MHz, CD₃OD) δ: 1.03 (t, J = 7.5 Hz, 3 H), 1.27 (t, J = I m/z 380 3-methyl-2-oxo-1-oxa-3,8- Example 7.0 Hz, 3 H), 1.62-2.39 (m, 16 H), 2.77-2.91 (m, 5 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 3.29-3.44 (m, 4 H), 4.12 (q, J = 7.0 Hz, 2 H) (ES+), at azaspiro[3.4]octane-6- Isomer 3 3.76 min, carboxylate UV inactive 4-20 Isomer 4: ethyl 2-(4-ethyl- 63 and e (400 MHz, CD₃OD) δ: 1.04 (t, J = 7.5 Hz, 3 H), 1.27 (t, J = I m/z 380 3-methyl-2-oxo-1-oxa-3,8- Example 7.0 Hz, 3 H), 1.62-2.35 (m, 14 H), 2.85-2.99 (m, 5 H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 3.30-3.44 (m, 4 H), 4.12 (q, J = 7.0 Hz, 2 H) 4.65 (s, 2 H) (ES+), at azaspiro[3.4]octane-6- Isomer 4 3.76 min, carboxylate UV inactive 4-21 Isomer 2 (racemic): methyl 46 and 49 e (400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.3 Hz, 3H), 1.03 (t, I m/z 380 2-(3,4-diethyl-2-oxo-1-oxa- J = 7.3 Hz, 3H), 1.24 (s, 1 H), 1.49-1.90 (m, 10H), 1.92-2.07 (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- (m, 4H), 2.55-2.76 (m, 4H), 2.99 (dd, J = 14.2, 7.2 (ES+), at yl)-6-azaspiro[3.4]octane-6- Hz, 1H), 3.12-3.20 (m, 2H), 3.28 (d, J = 5.5 Hz, 1H), 3.29 min, carboxylate 3.53-3.62 (m, 4H). UV inactive 4-22 Isomer 1: ethyl 2-(3,4- 46 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3H), 1.03 (t, I m/z 394 diethyl-2-oxo-1-oxa-3,8- Example J = 7.2 Hz, 3H), 1.12-1.29 (m, 5H), 1.45-1.83 (m, 10H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 1.89-2.16 (m, 4H), 2.52-2.73 (m, 3H), 2.93-3.06 (m, (ES+), at azaspiro[3.4]octane-6- Isomer 1 1 H), 3.13-3.39 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H) 3.87 min, carboxylate UV inactive 4-22 Isomer 2: ethyl 2-(3,4- 46 and e (400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3H), 1.03 (t, I m/z 394 diethyl-2-oxo-1-oxa-3,8- Example J = 7.0 Hz, 3H), 1.12-1.30 (m, 5H), 1.46-1.85 (m, 10H), (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 1.91-2.10 (m, 4H), 2.39-2.78 (m, 3H), 2.93-3.07 (m, (ES+), at azaspiro[3.4]octane-6- Isomer 2 1 H), 3.13-3.39 (m, 4H), 4.01 (q, J = 6.8 Hz, 2 H) 3.87 min, carboxylate UV inactive 4-22 Isomer 3: ethyl 2-(3,4- 46 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3H), 1.03 (t, I m/z 394 diethyl-2-oxo-1-oxa-3,8- Example J = 7.2 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 1.21-1.27 (m, (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 2H), 1.44-1.90 (m, 10H), 1.91-2.07 (m, 4H), 2.45-2.75 (ES+), at azaspiro[3.4]octane-6- Isomer 3 (m, 3H), 2.92-3.06 (m, 1H), 3.10-3.20 (m, 2H), 3.24-3.43 3.91 min, carboxylate (m, 2H), 4.00 (q, J = 7.1 Hz, 2H) UV inactive 4-22 Isomer 4: ethyl 2-(3,4- 46 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.3 Hz, 3H), 1.04 (t, I m/z 394 diethyl-2-oxo-1-oxa-3,8- Example J = 7.2 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H), 1.21-1.28 (m, (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 2H), 1.42-1.89 (m, 10H), 1.92-2.10 (m, 4H), 2.44-2.80 (ES+), at azaspiro[3.4]octane-6- Isomer 4 (m, 3H), 2.92-3.06 (m, 1H), 3.10-3.20 (m, 2H), 3.27-3.42 3.91 min, carboxylate (m, 2H), 4.00 (q, J = 7.2 Hz, 2H) UV inactive 4-23 Isomer 1: ethyl 2-(4-ethyl- 51 and e (400 MHz, DMSO-d₆) δ: 0.82-0.89 (m, 6 H), 1.15-1.19 I m/z 408 2-oxo-3-propyl-1-oxa-3,8- Example (m, 3 H), 1.24 (s, 1 H), 1.37-1.80 (m, 12 H), 2.00-2.05 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 4 H), 2.60-2.74 (m, 4 H), 2.89-2.96 (m, 1 H), 3.20-3.28 (ES+), at azaspiro[3.4]octane-6- Isomer 1 (m, 4 H), 4.01 (q, J = 7.0 Hz, 2 H), 4.21 min, carboxylate UV inactive 4-23 Isomer 2: ethyl 2-(4-ethyl- 51 and e (400 MHz, DMSO-d₆) δ: 0.82-0.89 (m, 6 H), 1.15-1.19 I m/z 408 2-oxo-3-propyl-1-oxa-3,8- Example (m, 3 H), 1.24 (s, 1 H), 1.37-1.80 (m, 12 H), 2.00-2.05 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 4 H), 2.60-2.74 (m, 4H), 2.89-2.96 (m, 1 H), 3.20-3.28 (ES+), at azaspiro[3.4]octane-6- Isomer 2 (m, 4 H), 4.01 (q, J = 7.0 Hz, 2 H) 4.21 min, carboxylate UV inactive 4-23 Isomer 3: ethyl 2-(4-ethyl- 51 and e (400 MHz, DMSO-d₆) δ: 0.82-0.89 (m, 6 H), 1.16 (t, J = I m/z 408 2-oxo-3-propyl-1-oxa-3,8- Example 7.0 Hz, 3 H), 1.24 (s, 1 H), 1.37-1.88 (m, 12 H), 1.97-2.02 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 4 H), 2.60-2.73 (m, 4 H), 2.89-2.96 (m, 1H), (ES+), at azaspiro[3.4]octane-6- Isomer 3 3.14-3.32 (m, 4 H), 4.00 (q, J = 7.0 Hz, 2 H) 4.26 min, carboxylate UV inactive 4-23 Isomer 4: ethyl 2-(4-ethyl- 51 and e (400 MHz, DMSO-d₆) δ: 0.81-0.89 (m, 6 H), 1.16 (t, J = I m/z 408 2-oxo-3-propyl-1-oxa-3,8- Example 7.0 Hz, 3 H), 1.24 (s, 1 H), 1.37-1.88 (m, 12 H), 1.97-2.02 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-12 (m, 4 H), 2.57-2.74 (m, 4 H), 2.89-2.96 (m, 1 H), (ES+), at azaspiro[3.4]octane-6- Isomer 4 3.14-3.31 (m, 4 H), 4.00 (q, J = 7.0 Hz, 2 H) 4.26 min, carboxylate UV inactive 4-24 Isomer 2 (racemic): ethyl 2- 53 and e (400 MHz, DMSO-d₆) δ: 0.79-0.91 (m, 9 H), 1.18 (s, 3 H), F m/z 420 [4-ethyl-3-(2-methylpropyl)- Example 1.25 (s, 2 H), 1.55-1.92 (m, 12 H), 2.09-1.95 (m, 4 H), (M + H)⁺ 2-oxo-1-oxa-3,8- 4-12 2.66-2.76 (m, 1 H), 2.78-2.86 (m, 1 H), 3.01-3.11 (m, 1 (ES+), at diazaspiro[4.5]dec-8-yl]-6- H), 3.16 (d, J = 6.7 Hz, 2 H), 3.24-3.33 (m, 2 H), 4.06-3.98 1.67 min, azaspiro[3.4]octane-6- (m, 2 H) UV inactive carboxylate 4-25 Isomer 2 (racemic): ethyl 2- 54 and e (400 MHz, DMSO-d₆) δ: 0.12-0.22 (m, 1 H), 0.22-0.33 F m/z 420 [3-(cyclopropylmethyl)-4- Example (m, 1 H), 0.38-0.47 (m, 1 H), 0.47-0.58 (m, 1 H), 0.89 (t, (M + H)⁺ ethyl-2-oxo-1-oxa-3,8- 4-12 J = 7.0 Hz, 3 H), 1.18 (t, J = 6.9 Hz, 3 H), 1.25 (s, 2 H), (ES+), at diazaspiro[4.5]dec-8-yl]-6- 1.59-1.93 (m, 11 H), 1.95-2.13 (m, 4 H), 2.79-2.92 (m, 1.68 min, azaspiro[3.4]octane-6- 2 H), 3.13-3.21 (m, 2 H), 3.23-3.32 (m, 2 H), 3.43-3.52 UV inactive carboxylate (m, 2 H), 3.97-4.06 (m, 2 H) 4-26 Isomer 2: methyl 2-(4,4- 11 and 20 b (400 MHz, DMSO-d₆) δ: 1.09 (s, 6H), 1.50-1.65 (m, 2H), G m/z 352 dimethyl-2-oxo-1-oxa-3,8- 1.65-1.79 (m, 4H), 1.79-1.94 (m, 4H), 1.96-2.04 (m, (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2H), 2.65-2.80 (m, 3H), 3.15 (s, 2H), 3.26-3.45 (m, 2H), (ES+), at azaspiro[3.4]octane-6- 3.56 (s, 3H), 7.52 (s, 1H) 4.31 min, carboxylate UV active 4-27 Isomer 1: ethyl 2-(4,4- 11 and 21 c (400 MHz, DMSO-d₆) δ: 1.09 (s, 6H), 1.13-1.24 (m, 3H), F m/z 366 dimethyl-2-oxo-1-oxa-3,8- 1.50-1.64 (m, 2H), 1.66-1.82 (m, 6H), 1.84-1.98 (m, (m + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 2H), 1.99-2.09 (m, 2H), 2.65-2.78 (m, 3H), 3.18-3.30 (ES+) at azaspiro[3.4]octane-6- (m, 4 H), 4.01 (q, J = 7.0, Hz, 2H), 7.52 (s, 1H) 2.15 min, carboxylate UV inactive 4-27 Isomer 2: ethyl 2-(4,4- 11 and 21 c (400 MHz, DMSO-d₆) δ: 1.09 (s, 6H), 1.16 (t, J = 7.0 Hz, F m/z 366 dimethyl-2-oxo-1-oxa-3,8- 3H), 1.51-1.66 (m, 2H), 1.67-1.80 (m, 4H), 1.81-1.93 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- (m, 4H), 1.94-2.08 (m, 2H), 2.65-2.74 (m, 3H), 3.15 (d, (ES+), at azaspiro[3.4]octane-6- J = 5.5 Hz, 2H), 3.22-3.32 (m, 2H), 4.00 (q, J = 7.0 Hz, 1.61 min, carboxylate 2H), 7.51 (s, 1H) UV active 4-28 Isomer 2: methyl 2-(12- 65 and 20 b (400 MHz, DMSO-d₆) δ: 1.48-1.58 (m, 1 H), 1.58-1.69 F m/z 364 oxo-11-oxa-8,13- (m, 2 H), 1.86 (m, 11 H), 1.98-2.08 (m, 2 H), 2.32-2.44 (M + H)⁺ diazadispiro[3.0.5.3]tridec- (m, 2 H), 2.66-2.79 (m, 3 H), 3.13-3.21 (m, 2 H), 3.26-3.33 (ES+), at 8-yl)-6-azaspiro[3.4]octane- (m, 2 H), 3.57 (s, 3 H), 8.26 (s, 1H) 1.63 min, 6-carboxylate UV active 4-29 Isomer 2: ethyl 2-(12-oxo- 65 and 21 b (400 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.0 Hz, 3 H), 1.48-1.57 F m/z 378 11-oxa-8,13- (m, 1 H), 1.57-1.66 (m, 2 H), 1.69-1.96 (m, 11 H), (M + H)⁺ diazadispiro[3.0.5.3]tridec- 1.97-2.06 (m, 2 H), 2.33-2.45 (m, 2 H), 2.67-2.78 (m, 3 H), (ES+), at 8-yl)-6-azaspiro[3.4]octane- 3.16 (d, J = 5.5 Hz, 2 H), 3.25-3.33 (m, 2 H), 4.01 (q, 1.70 min, 6-carboxylate J = 7.0 Hz, 2 H), 8.25 (s, 1 H) UV active 4-30 Isomer 1: ethyl 2-(2,2- 67 and 21 b (400 MHz, DMSO-d₆) δ: 1.15-1.20 (m, 3 H), 1.70-1.81 I m/z 414 difluoro-12-oxo-11-oxa- (m, 8 H), 1.90-1.95 (m, 2 H), 2.01-2.06 (m, 2 H), 2.60-2.76 (M + H)⁺ 8,13- (m, 5 H), 3.10-3.29 (m, 6 H), 4.01 (q, J = 7.0 Hz, 2 (ES+), at diazadispiro[3.0.5.3]tridec- H), 8.25 (s, 1 H) 3.57 min, 8-yl)-6-azaspiro[3.4]octane- UV inactive 6-carboxylate 4-30 Isomer 2: ethyl 2-(2,2- 67 and 21 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.71-2.09 I m/z 414 difluoro-12-oxo-11-oxa- (m, 12 H), 2.60-2.75 (m, 5 H), 3.10-3.20 (m, 4 H), (M + H)⁺ 8,13- 3.26-3.31 (m, 2 H), 4.00 (q, J = 7.0, 2 H), 8.25 (s, 1 H) (ES+), at diazadispiro[3.0.5.3]tridec- 3.61 min, 8-yl)-6-azaspiro[3.4]octane- UV inactive 6-carboxylate 4-31 Isomer 1: ethyl 2-(13-oxo- 69 and 21 b (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 H), 1.42-1.53 F m/z 392 12-oxa-9,14- (m, 2 H), 1.55-2.08 (m, 20 H), 2.65-2.77 (m, 3 H), (M + H)⁺ diazadispiro[4.0.5.3]tetradec- 3.12-3.20 (m, 2 H), 3.24-3.34 (m, 2 H), 4.01 (q, J = 7.0 (ES+), at 9-yl)-6- Hz, 2 H), 7.89 (s, 1 H) 1.60 min, azaspiro[3.4]octane-6- UV active carboxylate 4-31 Isomer 2: ethyl 2-(13-oxo- 69 and 21 b (400 MHz, DMSO-d₆) δ: 1.14-1.23 (m, 3 H), 1.40-1.54 F m/z 392 12-oxa-9,14- (m, 2 H), 1.54-1.85 (m, 16 H), 1.87-1.98 (m, 2 H), 1.98-2.10 (M + H)⁺ diazadispiro[4.0.5.3]tetradec- (m, 2 H), 2.65-2.79 (m, 3 H), 3.19-3.32 (m, 4 H), (ES+), at 9-yl)-6- 4.02 (q, J = 7.2 Hz, 2 H), 7.89 (s, 1 H) 1.62 min, azaspiro[3.4]octane-6- UV active carboxylate 4-32 Isomer 2: ethyl 2-(3,4,4- 63 and e (400 MHz, DMSO-d₆) δ: 1.10 (s, 6 H), 1.18 (t, J = 7.0 Hz, 3 H), I m/z 380 trimethyl-2-oxo-1-oxa-3,8- Example 1.68 (m, 10 H), 1.97-2.06 (m, 2 H), 2.63 (s, 3 H), 2.67-2.76 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-6- 4-27 (m, 3 H), 3.13-3.19 (m, 2 H), 3.25-3.33 (m, 2 H), (ES+), at azaspiro[3.4]octane-6- 3.97-4.06 (m, 2 H) 3.59 min, carboxylate UV inactive 4-33 Isomer 2: ethyl 2-[4,4- 70 and e (400 MHz, CD₃OD) δ: 1.19 (s, 6 H), 1.25 (t, J = 7.0 Hz, 3 H), I m/z 383 dimethyl-3-(²H₃)methyl-2- Example 1.68-1.80 (m, 2 H), 1.82-2.01 (m, 6 H), 2.07-2.20 (M + H)⁺ oxo-1-oxa-3,8- 4-27 (m, 4 H), 2.78-2.90 (m, 3 H), 3.23-3.30 (m, 2 H), 3.34-3.45 (ES+), at diazaspiro[4.5]dec-8-yl]-6- (m, 2 H), 4.05-4.14 (m, 2 H) 3.64 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-34 Isomer 2: methyl 2-(3-ethyl- 46 and e (400 MHz, CD₃OD) δ: 1.16-1.26 (m, 9 H), 1.69-1.80 (m, I m/z 380 4,4-dimethyl-2-oxo-1-oxa- Example 2 H), 1.83-2.02 (m, 6 H), 2.09-2.22 (m, 4 H), 2.78-2.93 (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-26 (m, 3 H), 3.20 (q, J = 7.0 Hz, 2 H), 3.29 (s, 2 H), 3.42 (t, (ES+), at yl)-6-azaspiro[3.4]octane-6- J = 5.8 Hz, 2 H), 3.69 (s, 3 H) 3.49 min, carboxylate UV inactive 4-35 Isomer 1: ethyl 2-(3-ethyl- 46 and e (400 MHz, DMSO-d₆) δ: 1.03-1.13 (m, 9 H), 1.17 (td, J = I m/z 394 4,4-dimethyl-2-oxo-1-oxa- Example 6.9, 2.9 Hz, 3 H), 1.54-1.81 (m, 8 H), 1.90 (t, J = 11.3 Hz, (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-27 2 H), 1.99-2.07 (m, 2 H), 2.70 (d, J = 11.3 Hz, 3 H), 3.07 (ES+), at yl)-6-azaspiro[3.4]octane-6- (q, J = 7.2 Hz, 2 H), 3.23 (q, J = 6.9 Hz, 2 H), 3.28 (d, J = 3.78 min, carboxylate 4.9 Hz, 2 H), 4.01 (q, J = 7.0 Hz, 2 H) UV inactive 4-35 Isomer 2: ethyl 2-(3-ethyl- 46 and e (400 MHz, DMSO-d₆) δ: 1.02-1.13 (m, 9 H), 1.16 (t, J = I m/z 394 4,4-dimethyl-2-oxo-1-oxa- Example 7.2 Hz, 3 H), 1.54-1.72 (m, 4 H), 1.76 (t, J = 9.8 Hz, 2 H), (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-27 1.80-1.96 (m, 4 H), 2.01 (t, J = 8.9 Hz, 2 H), 2.64-2.75 (ES+), at yl)-6-azaspiro[3.4]octane-6- (m, 3 H), 3.07 (q, J = 7.1 Hz, 2 H), 3.15 (d, J = 5.2 Hz, 2 H), 3.80 min, carboxylate 3.28 (q, J = 6.7 Hz, 2 H), 4.00 (q, J = 7.0 Hz, 2 H) UV inactive 4-36 Isomer 2: methyl 2-(4,4- 51 and e (400 MHz, CD₃OD) δ: 0.95 (t, J = 7.3 Hz, 3 H), 1.21 (s, I m/z 394 dimethyl-2-oxo-3-propyl-1- Example 6 H), 1.60-1.64 (m, 2 H), 1.69-1.81 (m, 2 H), 1.84-2.01 (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- 4-26 (m, 6 H), 2.10-2.22 (m, 4 H), 2.80-2.92 (m, 3 H), 3.09 (t, (ES+), at 8-yl)-6-azaspiro[3.4]octane- J = 7.5 Hz, 2 H), 3.29 (s, 2 H), 3.39-3.45 (m, 2 H), 3.68 3.77 min, 6-carboxylate (s, 3 H) UV inactive 4-37 Isomer 1: ethyl 2-(4,4- 51 and e (400 MHz, CD₃OD) δ: 0.95 (t, J = 7.3 Hz, 3 H), 1.15-1.38 I m/z 408 dimethyl-2-oxo-3-propyl-1- Example (m, 9 H), 1.53-1.69 (m, 2 H), 1.69-1.82 (m, 2 H), 1.82-1.98 (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- 4-27 (m, 5 H), 2.15-2.24 (m, 3 H), 2.80-2.95 (m, 3 H), (ES+), at 8-yl)-6-azaspiro[3.4]octane- 3.03-3.14 (m, 2 H), 3.35-3.42 (m, 4 H), 4.13 (q, J = 7.0 4.04 min, 6-carboxylate Hz, 2 H), 4.67 (br. s., 2 H) UV inactive 4-37 Isomer 2: ethyl 2-(4,4- 51 and e (400 MHz, CD₃OD) δ: 0.95 (t, J = 7.3 Hz, 3 H), 1.22 (s, 6 H), I m/z 408 dimethyl-2-oxo-3-propyl-1- Example 1.27 (t, J = 7.0 Hz, 3 H), 1.53-1.68 (m, 2 H), 1.68-1.82 (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- 4-27 (m, 2 H), 1.82-2.03 (m, 6 H), 2.06-2.24 (m, 4 H), (ES+), at 8-yl)-6-azaspiro[3.4]octane- 2.76-2.95 (m, 3 H), 3.01-3.14 (m, 2 H), 3.29 (br. s., 2 H), 4.07 min, 6-carboxylate 3.38-3.46 (m, 2 H), 4.12 (q, J = 7.0 Hz, 2 H) UV inactive 4-38 Isomer 1: ethyl 2-[4,4- 53 and e (400 MHz, CD₃OD) δ: 0.94 (d, J = 6.7 Hz, 6 H), 1.22 (s, 6 I m/z 422 dimethyl-3-(2- Example H), 1.24-1.30 (m, 4 H), 1.78-2.08 (m, 9 H), 2.19-2.29 (M + H)⁺ methylpropyl)-2-oxo-1-oxa- 4-27 (m, 2 H), 2.38 (t, J = 12.2 Hz, 2 H), 2.93 (d, J = 7.6 Hz, 2 H), (ES+), at 3,8-diazaspiro[4.5]dec-8- 2.99-3.14 (m, 3 H), 3.40 (dd, J = 16.2, 7.0 Hz, 3 H), 4.39 min, yl]-6-azaspiro[3.4]octane-6- 4.09-4.16 (m, 2 H) UV inactive carboxylate 4-38 Isomer 2: ethyl 2-[4,4- 53 and e (400 MHz, CD₃OD) δ: 0.94 (d, J = 6.7 Hz, 6 H), 1.22 (s, 6 H), I m/z 422 dimethyl-3-(2- Example 1.27 (t, J = 7.0 Hz, 4 H), 1.75-1.89 (m, 2 H), 1.91-2.10 (M + H)⁺ methylpropyl)-2-oxo-1-oxa- 4-27 (m, 7 H), 2.22 (br. s., 2 H), 2.36 (t, J = 11.7 Hz, 2 H), (ES+), at 3,8-diazaspiro[4.5]dec-8- 2.93 (d, J = 7.6 Hz, 2 H), 2.97-3.13 (m, 3 H), 3.30-3.31 4.42 min, yl]-6-azaspiro[3.4]octane-6- (m, 1 H), 3.42 (q, J = 6.7 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2 H) UV inactive carboxylate 4-39 Isomer 2: ethyl 2-[3- 54 and e (400 MHz, DMSO-d₆) δ: 0.20-0.24 (m, 2 H), 0.42-0.47 I m/z 420 (cyclopropylmethyl)-4,4- Example (m, 2 H), 0.92-1.01 (m, 1 H), 1.12 (s, 6 H), 1.16 (t, J = 7.0 Hz, (M + H)⁺ dimethyl-2-oxo-1-oxa-3,8- 4-27 3 H), 1.59-2.03 (m, 12 H), 2.70-2.72 (m, 3 H), 2.92 (ES+), at diazaspiro[4.5]dec-8-yl]-6- (d, J = 7.0 Hz, 2 H), 3.15 (d, J = 5.0 Hz, 2 H), 3.28 (m, 2 H), 4.24 min, azaspiro[3.4]octane-6- 4.00 (q, J = 7.0 Hz, 2 H) UV inactive carboxylate 4-40 Isomer 2: ethyl 2-[3-(2- 54 and e (400 MHz, CD₃OD) δ: 1.22 (s, 6 H), 1.27 (t, J = 7.0 Hz, 3 H), I m/z 412 fluoroethyl)-4,4-dimethyl-2- Example 1.72-1.80 (m, 2 H), 1.89-2.00 (m, 6 H), 2.11-2.19 (M + H)⁺ oxo-1-oxa-3,8- 4-27 (m, 4 H), 2.84-2.90 (m, 3 H), 3.29 (s, 2H), 3.39-3.49 (m, (ES+), at diazaspiro[4.5]dec-8-yl]-6- 4 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.53 (dt, J = 47.5, 5.0 Hz, 2 H) 3.83 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-41 Isomer 2: ethyl 2-[3-(2- 71 and e (400 MHz, CD₃OD) δ: 1.21 (s, 6 H), 1.27 (t, J = 7.0 Hz, 3 H), I m/z 424 methoxyethyl)-4,4- Example 1.71-1.78 (m, 2H), 1.88-2.00 (m, 6 H), 2.11-2.19 (M + H)⁺ dimethyl-2-oxo-1-oxa-3,8- 4-27 (m, 4 H), 2.83-2.89 (m, 3 H), 3.29-3.31 (m, 4 H), 3.36 (ES+), at diazaspiro[4.5]dec-8-yl]-6- (s, 3 H), 3.41 (q, J = 6.5 Hz, 2 H), 3.52 (t, J = 5.5 Hz, 2 H), 3.67 min, azaspiro[3.4]octane-6- 4.11 (q, J = 7.0 Hz, 2 H) UV inactive carboxylate 4-42 Isomer 2: ethyl 2-[3- 72 and e (400 MHz, CD₃OD) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.32 (s, 6 H), I m/z 405 (cyanomethyl)-4,4- Example 1.74-1.82 (m, 2 H), 1.89-2.00 (m, 6 H), 2.11-2.18 (M + H)⁺ dimethyl-2-oxo-1-oxa-3,8- 4-27 (m, 4 H), 2.84-2.90 (m, 3 H), 3.29 (s, 2 H), 3.42 (q, J = (ES+), at diazaspiro[4.5]dec-8-yl]-6- 6.5 Hz, 2 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.29 (s, 2 H) 3.77 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-43 Isomer 2: ethyl 2-[4,4- 73 and e (400 MHz, CD₃OD) δ: 1.24-1.31 (m, 9 H), 1.75-1.83 (m, I m/z 448 dimethyl-2-oxo-3-(2,2,2- Example 2H), 1.88-1.95 (m, 6 H), 2.13-2.20 (m, 4 H), 2.85-2.91 (M + H)⁺ trifluoroethyl)-1 -oxa-3,8- 4-27 (m, 3 H), 3.36-3.41 (m, 4 H), 3.93 (q, J = 9.0 Hz, 2 H), (ES+), at diazaspiro[4.5]dec-8-yl]-6- 4.13 (q, J = 7.0 Hz, 2 H) 4.21 min, azaspiro[3.4]octane-6- UV inactive carboxylate 4-44 Isomer 2 (racemic): ethyl 2- 21 and 76 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.36-1.46 I m/z 378 (3′-oxotetrahydro-1H- (m, 1 H), 1.76-1.86 (m, 13 H), 1.97-2.02 (m, 3 H), (M + H)⁺ spiro[piperidine-4,1′- 2.11-2.22 (m, 1 H), 2.68-2.72 (m, 1 H), 3.04-3.10 (m, 1 H), (ES+), at pyrrolo[1,2-c][1,3]oxazol]-1- 3.15 (d, J = 6.0 Hz, 2 H), 3.25-3.38 (m, 3 H), 3.51-3.55 3.70 min, yl)-6-azaspiro[3.4]octane-6- (m, 1 H), 3.99 (q, J = 7.0 Hz, 2 H) UV inactive carboxylate 4-44 Isomer 3: ethyl 2-(3′- 21 and 76 b (400 MHz, CD₃OD) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.55-1.59 I m/z 378 oxotetrahydro-1H- (m, 1 H), 1.76-2.09 (m, 11 H), 2.10-2.41 (m, 5 H), 2.63-2.75 (M + H)⁺ spiro[piperidine-4,1′- (m, 1 H), 2.81-2.88 (m, 1 H), 3.15-3.24 (m, 1 H), (ES+), at pyrrolo[1,2-c][1,3]oxazol]-1- 3.36-3.44 (m, 3 H), 3.49-3.56 (m, 2 H), 3.61-3.70 (m, 3.63 min, yl)-6-azaspiro[3.4]octane-6- 1 H), 4.10(q, J = 7.0 Hz, 2 H) UV inactive carboxylate 4-44 Isomer 4: ethyl 2-(3′- 21 and 76 b (400 MHz, CD₃OD) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.55-1.59 I m/z 378 oxotetrahydro-1H- (m, 1 H), 1.76-2.09 (m, 11 H), 2.10-2.40 (m, 5 H), 2.66-2.74 (M + H)⁺ spiro[piperidine-4,1′- (m, 1 H), 2.81-2.87 (m, 1 H), 3.15-3.23 (m, 1 H), (ES+), at pyrrolo[1,2-c][1,3]oxazol]-1- 3.36-3.44 (m, 3 H), 3.49-3.56 (m, 2 H), 3.61-3.69 (m, 3.63 min, yl)-6-azaspiro[3.4]octane-6- 1 H), 4.10 (q, J = 7.0 Hz, 2 H) UV inactive carboxylate 4-45 Isomer 2 (racemic): methyl 20 and 76 b (400 MHz, CD₃OD) δ: 1.47-1.61 (m, 1 H), 1.76-2.09 (m, I m/z 364 2-(3′-oxotetrahydro-1H- 11 H), 2.10-2.40 (m, 5 H), 2.53-2.72 (m, 1 H), 2.79-2.91 (M + H)⁺ spiro[piperidine-4,1′- (m, 1 H), 3.17-3.23 (m, 1 H), 3.39-3.43 (m, 3 H), (ES+), at pyrrolo[1,2-c][1,3]oxazol]-1- 3.49-3.54 (m, 2 H), 3.61-3.67 (m, 1 H), 3.68 (s, 3 H) 3.31 min, yl)-6-azaspiro[3.4]octane-6- UV inactive carboxylate 4-46 Isomer 1: ethyl 2-[4-ethyl-3- 70 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.3 Hz, 3 H), 1.18 (t, I m/z 383 (²H₃)methyl-2-oxo-1-oxa- Example J = 7.0 Hz, 3 H), 1.23-1.31 (m, 1 H), 1.46-1.83 (m, 9 H), (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-7 1.91-2.09 (m, 4 H), 2.53-2.78 (m, 3 H), 3.12-3.31 (m, (ES+), at yl]-6-azaspiro[3.4]octane-6- Isomer 1 5 H), 4.01 (q, J = 7.1 Hz, 2 H). 3.52 min, carboxylate UV inactive 4-46 Isomer 3: ethyl 2-[4-ethyl-3- 70 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.16 (t, I m/z 383 (²H₃)methyl-2-oxo-1-oxa- Example J = 7.1 Hz, 3 H), 1.21-1.28 (m, 1 H), 1.47-1.89 (m, 9 H), (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-7 1.91-2.05 (m, 4 H), 2.54-2.76 (m, 3 H), 3.12-3.18 (m, (ES+), at yl]-6-azaspiro[3.4]octane-6- Isomer 3 2 H), 3.20-3.32 (m, 3 H), 4.00 (q, J = 7.1 Hz, 2 H). 3.70 min, carboxylate UV inactive 4-46 Isomer 4: ethyl 2-[4-ethyl-3- 70 and e (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.16 (t, I m/z 383 (²H₃)methyl-2-oxo-1-oxa- Example J = 7.0 Hz, 3 H), 1.22-1.29 (m, 1 H), 1.47-1.90 (m, 9 H), (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 4-7 1.91-2.07 (m, 4 H), 2.54-2.77 (m, 3 H), 3.11-3.19 (m, (ES+), at yl]-6-azaspiro[3.4]octane-6- Isomer 4 2 H), 3.21-3.31 (m, 3 H), 4.00 (q, J = 7.0 Hz, 2 H). 3.65 min, carboxylate UV inactive 4-47 Mixture of diastereomers: 21 and 83 g (400 MHz, CDCl₃) δ: 0.50-0.64 (m, 1 H), 0.65-0.77 (m, 1 H), P m/z 406 ethyl 2-(3-cyclopropyl-4- 0.79-0.87 (m, 1 H), 0.89-0.98 (m, 1 H), 1.04 (t, J = (M + H)⁺ ethyl-2-oxo-1-oxa-3,8- 7.4 Hz, 3 H), 1.19-1.29 (m, 3 H), 1.59-2.00 (m, 10 H), (ES+), at diazaspiro[4.5]dec-8-yl)-6- 2.01-2.31 (m, 4 H), 2.39-2.48 (m, 1 H), 2.60-2.84 (m, 3 H), 2.33 min, azaspiro[3.4]octane-6- 3.20-3.46 (m, 5 H), 4.02-4.23 (m, 2 H) UV inactive carboxylate 4-48 Mixture of diastereomers: 21 and 85 g (400 MHz, CDCl₃) δ: 1.07 (t, J = 7.6 Hz, 3 H), 1.20-1.33 P m/z 396 ethyl 2-(4-ethyl-3-methoxy- (m, 3 H), 1.58-1.73 (m, 2 H), 1.73-1.96 (m, 8 H), 2.01-2.25 (M + H)⁺ 2-oxo-1-oxa-3,8- (m, 4 H), 2.64-2.82 (m, 3 H), 3.20-3.50 (m, 5 H), (ES+), at diazaspiro[4.5]dec-8-yl)-6- 3.82 (s, 3 H), 4.05-4.22 (m, 2 H) 2.36 min and azaspiro[3.4]octane-6- 2.38 min, carboxylate UV inactive 5-1 Mixture of diastereomers: 12 and 20 a (400 MHz, CDCl₃) δ: 1.67-1.97 (m, 8 H), 2.03-2.16 (m, 2 H), B m/z 323 methyl 2-(2-oxo-1,3,8- 2.16-2.38 (m, 3 H), 2.55-2.75 (m, 1 H), 3.17-3.47 (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- (m, 7 H), 3.63-3.71 (m, 3 H), 4.45 (br. s., 1 H), 4.79 (br. s., (ES+), at azaspiro[3.4]octane-6- 1 H) 1.84 min and carboxylate 1.99 min, UV inactive 5-2 Isomer 1: ethyl 2-(2-oxo- 12 and 21 a (400 MHz, DMSO-d₆) δ: 1.09-1.20 (m, 3 H), 1.53 (t, J = B m/z 337 1,3,8-triazaspiro[4.5]dec-8- 5.0 Hz, 4 H), 1.62-1.85 (m, 4 H), 1.85-2.08 (m, 4 H), (M + H)⁺ yl)-6-azaspiro[3.4]octane-6- 2.33-2.44 (m, 2 H), 2.54-2.64 (m, 1 H), 3.02 (s, 2 H), (ES+), at carboxylate 3.13-3.25 (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 6.06 (s, 1 2.16 min, H), 6.48 (br. s., 1 H) UV inactive 5-2 Isomer 2: ethyl 2-(2-oxo- 12 and 21 a (400 MHz, DMSO-d₆) δ: 0.85 (t, J = 7.5 Hz, 3 H), 1.24 (t, B m/z 337 1,3,8-triazaspiro[4.5]dec-8- J = 5.0 Hz, 4 H), 1.43 (t, J = 9.5 Hz, 2 H), 1.47-1.57 (m, 2 (M + H)⁺ yl)-6-azaspiro[3.4]octane-6- H), 1.58-1.86 (m, 4 H), 1.98-2.15 (m, 2 H), 2.28-2.39 (ES+), at carboxylate (m, 1 H), 2.73 (s, 2 H), 2.83 (d, J = 5.5 Hz, 2 H), 2.93-2.98 2.28 min, (m, 2 H), 3.68 (q, J = 7.5 Hz, 2 H), 5.79 (s, 1 H), 6.21 UV inactive (br. s., 1 H) 6-1 Isomer 2: methyl 2-(1-ethyl- 13 and 20 b (400 MHz, DMSO-d₆) δ: 0.97 (t, J = 7.0 Hz, 3 H), 1.62-2.33 I m/z 351 3-oxo-1,2,8- (m, 17 H), 2.60-2.68 (m, 2 H), 3.13-3.18 (m, 2 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 3.26-3.30 (m, 2 H), 3.56 (s, 3 H), 9.46 (s, 1 H) (ES+), at azaspiro[3.4]octane-6- 2.84 min, carboxylate UV inactive 6-2 Isomer 2: ethyl 2-(1-ethyl- 13 and 21 b (400 MHz, DMSO-d₆) δ: 0.97 (t, J = 7.0 Hz, 3H), 1.10-1.25 G m/z 365 3-oxo-1,2,8- (m, 6H), 1.50-2.99 (m, 12H), 3.01-3.44 (m, 6H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 3.92-4.09 (m, 4H), 9.46 (s, 1H) (ES+), at azaspiro[3.4]octane-6- 4.33 min, carboxylate UV active 6-3 Isomer 2: methyl 2-(3-oxo- 20 and 78 b (400 MHz, DMSO-d₆) δ: 0.86 (t, J = 7.5 Hz, 3 H), 1.37-2.39 I m/z 365 1-propyl-1,2,8- (m, 16 H), 2.60-2.68 (m, 5 H), 3.13-3.17 (m, 2 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 3.26-3.30 (m, 2 H), 3.55 (s, 3 H), 9.46 (s, 1 H) (ES+), at azaspiro[3.4]octane-6- 3.16 min, carboxylate UV inactive 6-4 Isomer 2: ethyl 2-(3-oxo-1- 21 and 78 b (400 MHz, DMSO-d₆) δ: 0.86 (t, J = 7.3 Hz, 3 H), 1.16 (t, I m/z 379 propyl-1,2,8- J = 7.0 Hz, 3 H), 1.27-1.50 (m, 2 H), 1.50-1.70 (m, 4 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 1.70-1.90 (m, 5 H), 1.90-2.27 (m, 6 H), 2.29-2.46 (m, 2 H), (ES+), at azaspiro[3.4]octane-6- 2.56-2.77 (m, 2 H), 3.21 -3.31 (m, 2 H), 3.27 (d, J = 3.41 min, carboxylate 6.4 Hz, 2 H), 3.99 (q, J = 7.0 Hz, 2 H), 9.46 (s, 1 H) UV inactive 6-5 Isomer 2: ethyl 2-[3-oxo-1- 21 and 80 b (400 MHz, CD₃OD) δ: 1.17 (d, J = 6.7 Hz, 6 H), 1.24-1.29 I m/z 379 (propan-2-yl)-1,2,8- (m, 3 H), 1.61-1.84 (m, 4 H), 1.84-2.01 (m, 4 H), 2.13-2.21 (M + H)⁺ triazaspiro[4.5]dec-8-yl]-6- (m, 3 H), 2.37-2.57 (m, 5 H), 2.79-2.96 (m, 1 H), (ES+), at azaspiro[3.4]octane-6- 3.38 (dd, J = 13.6, 6.3 Hz, 4 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.52 min, carboxylate 4.21-4.36 (m, 1 H) UV inactive NH not observed 6-6 Isomer 1: ethyl 2-(1-benzyl- 14 and 21 b (400 MHz, CDCl₃) δ: 0.76-0.95 (m, 3H), 1.21-1.34 (m, D m/z 427 3-oxo-1,2,8- 6H), 1.49-2.28 (m, 9H), 2.36-2.82 (m, 4H), 3.23-3.52 (m + H)⁺ triazaspiro[4.5]dec-8-yl)-6- (m, 4H), 3.79-3.91 (m, 1 H), 4.15 (q, J = 7.0 Hz, 2H), (ES+) at azaspiro[3.4]octane-6- 7.24-7.43 (m, 5H) 2.91 min, carboxylate UV inactive 6-6 Isomer 2: ethyl 2-(1-benzyl- 14 and 21 b (400 MHz, CDCl₃) 0.79-0.95 (m, 3H), 1.16-1.41 (m, 6H), D m/z 427 3-oxo-1,2,8- 1.52-2.17 (m, 9H), 2.37-2.83 (m, 4H), 3.23-3.52 (m, (m + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 4H), 3.79-3.93 (m, 1H), 4.14 (q, J = 7.0 Hz, 2H), 7.24-7.44 (ES+) at azaspiro[3.4]octane-6- (m, 5H) 3.04 min, carboxylate UV inactive 6-7 Isomer 2: ethyl 2-(1-ethyl- 63 and b (400 MHz, CD₃OD) δ: 1.12 (t, J = 7.1 Hz, 3 H), 1.26 (t, J = I m/z 379 2-methyl-3-oxo-1,2,8- Example 7.0 Hz, 3 H), 1.65-1.87 (m, 4 H), 1.88-2.02 (m, 4 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 6-1 2.07-2.36 (m, 4 H), 2.39-2.69 (m, 4 H), 2.82 (quint, J = (ES+), at azaspiro[3.4]octane-6- 7.9 Hz, 1 H), 2.96-3.11 (m, 5 H), 3.28 (s, 2 H), 3.41 (q, 3.38 min, carboxylate J = 6.5 Hz, 2 H), 4.11 (q, J = 7.1 Hz, 2 H) UV inactive 6-8 Isomer 2: ethyl 2-(1,2- 46 and b (400 MHz, CD₃OD) δ: 1.10 (t, J = 7.2 Hz, 3 H), 1.16 (t, J = I m/z 393 diethyl-3-oxo-1,2,8- Example 7.2 Hz, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.65-2.01 (m, 8 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 6-1 2.10-2.20 (m, 3 H), 2.39-2.79 (m, 4 H), 2.86 (quint., J = (ES+), at azaspiro[3.4]octane-6- 7.9 Hz, 1 H), 3.04 (q, J = 7.0 Hz, 2 H), 3.29 (s, 2 H), 3.37 3.60 min, carboxylate (s, 1 H), 3.38-3.54 (m, 4 H), 4.11 (q, J = 7.0 Hz, 2 H) UV inactive 6-9 Isomer 2: ethyl 2-(1-ethyl- 51 and b (400 MHz, CD₃OD) δ: 0.95 (t, J = 7.3 Hz, 3 H), 1.08 (t, J = I m/z 407 3-oxo-2-propyl-1,2,8- Example 7.2 Hz, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.63 (dq, J = 14.9, (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 6-1 7.4 Hz, 2 H), 1.68-2.03 (m, 10 H), 2.06-2.23 (m, 3 H), (ES+), at azaspiro[3.4]octane-6- 2.35-2.70 (m, 4 H), 2.82 (quint., J = 7.9 Hz, 1 H), 3.06 (q, 3.99 min, carboxylate J = 6.7 Hz, 2 H), 3.29 (s, 2 H), 3.40 (dt, J = 13.3, 6.5 Hz, 3 H), UV inactive 4.11 (q, J = 7.1 Hz, 2 H) 6-10 Isomer 2: ethyl 2-(2-methyl- 63 and b (400 MHz, CD₃OD) δ: 0.99 (t, J = 7.3 Hz, 3 H), 1.27 (t, J = I m/z 392 3-oxo-1-propyl-1,2,8- Example 7.1 Hz, 3 H), 1.55-1.59 (m, J = 7.6 Hz, 2 H), 1.66-1.89 (M + H)⁺ triazaspiro[4.5]dec-8-yl)-6- 6-4 (m, 4 H), 1.92-2.00 (m, 4 H), 2.09-2.40 (m, 4 H), 2.40-2.56 (ES+), at azaspiro[3.4]octane-6- (m, 2 H), 2.56-2.70 (m, 1 H), 2.78-2.93 (m, 3 H), 3.72 min, carboxylate 3.05 (s, 3 H), 3.29 (s, 2 H), 3.36-3.46 (m, 3 H), 4.11 (q, UV inactive J = 6.8 Hz, 2 H) 6-11 Isomer 2: ethyl 2-[2- 70 and b (400 MHz, CD₃OD) δ: 0.99 (t, J = 7.3 Hz, 3 H), 1.27 (t, J = I m/z 396 (²H₃)methyl-3-oxo-1-propyl- Example 7.1 Hz, 3 H), 1.56 (dq, J = 15.0, 7.4 Hz, 2 H), 1.68-1.87 (M + H)⁺ 1,2,8-triazaspiro[4.5]dec-8- 6-4 (m, 4 H), 1.87-2.01 (m, 4 H), 2.07-2.33 (m, 4 H), 2.44-2.55 (ES+), at yl]-6-azaspiro[3.4]octane-6- (m, 2 H), 2.55-2.66 (m, 1 H), 2.76-2.92 (m, 3 H), 3.80 min, carboxylate 3.28 (s, 2 H), 3.40 (dt, J = 13.0, 6.2 Hz, 3 H), 4.11 (q, J = UV inactive 7.1 Hz, 2 H) 6-12 Isomer 1: ethyl 2-[1-ethyl-2- 21 and 87 b (400 MHz, CD₃OD) δ: 1.12 (t, J = 7.1 Hz, 3 H), 1.21-1.42 I m/z 382 (²H₃)methyl-3-oxo-1,2,8- (m, 4 H), 1.67-1.84 (m, 4 H), 1.84-1.98 (m, 5 H), 2.06-2.32 (M + H)⁺ triazaspiro[4.5]dec-8-yl]-6- (m, 4 H), 2.46-2.48 (m, 1 H), 2.61-2.63 (m, 1 H), (ES+), at azaspiro[3.4]octane-6- 2.75-2.86 (m, 1 H), 3.02 (q, J = 6.8 Hz, 2 H), 3.35-3.48 3.19 min, carboxylate (m, 4 H), 4.12 (q, J = 6.9 Hz, 2 H) UV inactive 6-12 Isomer 2: ethyl 2-[1-ethyl-2- 21 and 87 b (400 MHz, CD₃OD) δ: 1.12 (t, J = 7.1 Hz, 3 H), 1.27 (t, I m/z 382 (²H₃)methyl-3-oxo-1,2,8- J = 7.1 Hz, 3 H), 1.28-1.36 (m, 2 H), 1.68-1.87 (m, 4 H), (M + H)⁺ triazaspiro[4.5]dec-8-yl]-6- 1.87-2.04 (m, 5 H), 2.07-2.32 (m, 4 H), 2.47-2.53 (m, 1 (ES+), at azaspiro[3.4]octane-6- H), 2.81 (quint., J = 7.8 Hz, 1 H), 3.02 (q, J = 7.0 Hz, 2 H), 3.31 min, carboxylate 3.36-3.49 (m, 4 H), 4.11 (q, J = 7.0 Hz, 2 H) UV inactive 7-1 Racemic: ethyl 6-(3-oxo- 45 and 1 a (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.38-1.60 B m/z 336 2,8-diazaspiro[4.5]dec-8- (m, 6 H), 1.68-1.84 (m, 3 H), 1.98 (s, 2 H), 2.00-2.03 (M + H)⁺ yl)-2-azaspiro[3.4]octane-2- (m, 1 H), 2.20-2.40 (m, 4 H), 2.53-2.58 (m, 1 H), (ES+), at carboxylate 2.98 (s, 2 H), 3.60-3.79 (m, 4 H), 3.97 (q, J = 7.0 Hz, 2 H), 2.26 min, 7.45 (s, 1 H) UV inactive 8-1 Mixture of diastereomers: 45 and 9 b (400 MHz, DMSO-d₆) δ: 0.89 (t, J = 7.5 Hz, 3 H), 1.15 (t, I m/z 366 ethyl 6-(4-ethyl-2-oxo-1- J = 7.0 Hz, 3 H), 1.24-1.30 (m, 1 H), 1.39-1.52 (m, 2 H), (M + H)⁺ oxa-3,8-diazaspiro[4.5]dec- 1.56-1.84 (m, 8 H), 2.00-2.30 (m, 3 H), 2.53-2.58 (m, 1 H), (ES+), at 8-yl)-2-azaspiro[3.4]octane- 2.64-2.72 (m, 2 H), 3.19-3.24 (m, 1 H), 3.67-3.80 3.39 min, 2-carboxylate (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 7.80 (s, 1 H) UV inactive 8-2 Mixture of diastereomers: 46 and e 400 MHz, DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3 H), 1.03 (t, I m/z 394 ethyl 6-(3,4-diethyl-2-oxo- Example J = 7.0 Hz, 3 H), 1.15 (t, J = 7.0 Hz, 3 H), 1.42-1.49 (m, 2 H), (M + H)⁺ 1-oxa-3,8- 8-1 1.54-1.84 (m, 8 H), 2.00-2.25 (m, 3 H), 2.54-2.62 (ES+), at diazaspiro[4.5]dec-8-yl)-2- (m, 3 H), 2.66-2.75 (m, 2 H), 2.95-3.03 (m, 1 H), 3.40-3.45 3.84 min, azaspiro[3.4]octane-2- (m, 1 H), 3.68-3.82 (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H) UV inactive carboxylate 8-3 Racemic: ethyl 6-(4,4- 45 and 11 b 400 MHz, DMSO-d₆) δ: 1.09 (s, 6 H), 1.14 (t, J = 7.0 Hz, 3 H), I m/z 366 dimethyl-2-oxo-1-oxa-3,8- 1.38-1.41 (m, 1 H), 1.57-1.84 (m, 8 H), 1.97-2.10 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- (m, 3 H), 2.56-2.61 (m, 1 H), 2.74-2.86 (m, 2 H), 3.68-3.82 (ES+), at azaspiro[3.4]octane-2- (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 7.51 (s, 1 H) 3.32 min, carboxylate UV inactive 8-3 Isomer 1: ethyl 6-(4,4- 45 and 11 b 400 MHz, DMSO-d₆) δ: 1.10 (s, 6 H), 1.15 (t, J = 7.0 Hz, 3 H), I m/z 366 dimethyl-2-oxo-1-oxa-3,8- 1.39-1.42 (m, 1 H), 1.57-1.84 (m, 8 H), 1.97-2.10 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- (m, 3 H), 2.56-2.62 (m, 1 H), 2.74-2.86 (m, 2 H), 3.68-3.82 (ES+), at azaspiro[3.4]octane-2- (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 7.51 (s, 1 H) 3.28 min, carboxylate UV inactive 8-3 Isomer 2: ethyl 6-(4,4- 45 and 11 b 400 MHz, DMSO-d₆) δ: 1.09 (s, 6 H), 1.15 (t, J = 7.0 Hz, 3 H), I m/z 366 dimethyl-2-oxo-1-oxa-3,8- 1.38-1.41 (m, 1 H), 1.57-1.85 (m, 8 H), 1.99-2.10 (M + H)⁺ diazaspiro[4.5]dec-8-yl)-2- (m, 3 H), 2.56-2.61 (m, 1 H), 2.75-2.86 (m, 2 H), 3.68-3.82 (ES+), at azaspiro[3.4]octane-2- (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H), 7.51 (s, 1 H) 3.28 min, carboxylate UV inactive 8-4 Racemic: ethyl 6-(3-ethyl- 46 and e 400 MHz, DMSO-d₆) δ: 1.06 (t, J = 7.0 Hz, 3 H), 1.09 (s, 6 H), I m/z 394 4,4-dimethyl-2-oxo-1-oxa- Example 1.15 (t, J = 7.0 Hz, 3 H), 1.37-1.43 (m, 1 H), 1.56-1.85 (M + H)⁺ 3,8-diazaspiro[4.5]dec-8- 8-3 (m, 8 H), 1.99-2.10 (m, 3 H), 2.56-2.61 (m, 1 H), (ES+), at yl)-2-azaspiro[3.4]octane-2- 2.75-2.86 (m, 2 H), 3.06 (q, J = 7.0 Hz, 2 H), 3.68-3.82 3.70 min, carboxylate (m, 4 H), 3.98 (q, J = 7.0 Hz, 2 H) UV inactive

Biological Activity Example A Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefire phospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High Throughput Screen, 2008). ERK1/2 phosphorylation is a downstream consequence of both Gq/11 and Gi/o protein coupled receptor activation, making it highly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄ receptors (Gi/o coupled), rather than using different assay formats for different receptor subtypes. CHO cells stably expressing the human muscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-well tissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cells were serum-starved overnight. Agonist stimulation was performed by the addition of 5 μL agonist to the cells for 5 min (37° C.). Media was removed and 50 μL of lysis buffer added. After 15 min, a 4 μL sample was transferred to 384-well plate and 7 μL of detection mixture added. Plates were incubated for 2 h with gentle agitation in the dark and then read on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data for each receptor subtype.

For some examples two or more diastereomers exist which have been separated, unless stated otherwise, and assigned based on their retention time on LCMS analytical trace. In most examples, isomer 1 is not active. Analytical data for active isomers is reported in Table 3. Data for several weakly active compounds are included in Table 3 and 4 to highlight preference of absolute stereochemistry.

The results are set out in Table 4 below.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ pEC₅₀ M₃ pEC₅₀ M₄ (% Emax (% Emax (% Emax (% Emax Ex. No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh 8.3 (102) 7.8 (105) 8.1 (115) 8.1 (110) 1-1 6.5 (107) NT NT <4.7 (66) 2-1 Isomer 1 6.6 (107) <4.7 (15) <4.7 (9) 6.9 (117) 2-1 Isomer 2 6.8 (106) <4.7 (15) <4.7 (4) 6.9 (108) 2-2 racemic 5.7 (74) <4.7 (71) <4.7 (27) 6.7 (69) 2-3 5.5 (92) NT NT 6.0 (73) 2-4 6.0 (56) <4.7 (14) <4.7 (24) 6.3 (95) 2-5 6.0 (28) NT NT 6.9 (34) 3-1 Isomer 2 7.1 (87) <4.7 (14) <4.7 (20) 7.0 (50) 3-2 Isomer 2 7.8 (87) <4.7 (3) <4.7 (2) 7.7 (50) 3-3 Isomer 2 6.8 (97) <4.7 (2) <4.7 (7) 6.7 (81) 3-4 Isomer 1 5.5 (35) NT NT 6.5 (30) 3-4 Isomer 2 5.7 (71) NT NT 6.7 (36) 3-4 Isomer 3 7.1 (101) <4.7 (8) <4.7 (24) 7.6 (71) 3-4 Isomer 4 7.2 (90) <4.7 (20) <4.7 (17) 8.2 (76) 3-5 Isomer 2 7.6 (96) <4.7 (16) <4.7 (10) 8.5 (108) 3-7 Isomer 2 7.6 (101) <4.7 (11) <4.7 (14) 7.1 (57) 3-8 Isomer 2 7.9 (110) <4.7 (33) <4.7 (53) 7.1 (98) 3-9 Isomer 2 6.1 (62) <4.7 (4) <4.7 (14) <4.7 (47) 4-1 Isomer 2 6.9 (104) <4.7 (18) <4.7 (11) 6.9 (86) 4-2 Isomer 2 6.6 (113) <4.7 (13) <4.7 (42) 6.7 (76) 4-3 Isomer 1 6.6 (91) NT NT 6.5 (37) 4-3 Isomer 2 7.7 (116) <4.7 (0) <4.7 (7) 7.4 (78) 4-4 Isomer 2 6.2 (52) NT NT 6.4 (24) 4-5 Isomer 2 6.1 (50) NT NT 6.4 (74) 4-6 Isomer 2 6.0 (66) NT NT 6.1 (91) 4-7 Isomer 2 6.2 (104) <4.7 (41) <4.7 (2) 6.3 (69) 4-8 Isomer 2 5.9 (63) NT NT 6.4 (58) 4-9 Isomer 2 6.0 (104) NT NT 6.2 (76) 4-10 Isomer 2 6.0 (65) NT NT 6.1 (42) 4-11 Isomer 2 6.8 (114) <4.7 (7) <4.7 (7) 7.1 (102) 4-12 Isomer 1 <4.7 (17) <4.7 (50) <4.7 (4) 7.1 (63) 4-12 Isomer 2 <4.7 (0) NT NT <4.7 (1) 4-12 Isomer 3 7.6 (111) <5.2 (20) <4.7 (8) 8.2 (118) 4-15 Isomer 1 6.3 (85) NT NT 6.8 (87) (racemic) 4-17 Isomer 1 6.9 (114) <4.7 (54) <4.7 (14) 7.5 (107) (racemic) 4-19 Isomer 2 6.7 (98) NT NT 6.1 (72) (racemic) 4-20 Isomer 1 5.7 (57) NT NT 6.3 (42) 4-20 Isomer 2 <4.7 (16) NT NT <4.7 (9) 4-20 Isomer 3 6.8 (97) <4.7 (10) <4.7 (4) 7.5 (59) 4-21 Isomer 2 6.1 (77) NT NT 6.7 (36) (racemic) 4-22 Isomer 1 <4.7 (13) NT NT <4.7 (18) 4-22 Isomer 2 <4.7 (1) NT NT <4.7 (2) 4-22 Isomer 3 6.7 (95) <4.7 (3) <4.7 (1) 7.5 (80) 4-22 Isomer 4 6.7 (104) <4.7 (23) <4.7 (2) 7.3 (113) 4-23 Isomer 1 <4.7 (9) NT NT 6.3 (33) 4-23 Isomer 2 <4.7 (5) NT NT <4.7 (3) 4-23 Isomer 3 6.5 (88) <4.7 (8) <4.7 (4) 7.3 (32) 4-23 Isomer 4 6.5 (96) <4.7 (8) <4.7 (3) 8.0 (109) 4-24 Isomer 2 6.3 (84) <4.7 (53) <4.7 (2) 8.0 (84) (racemic) 4-25 Isomer 2 6.1 (73) NT NT 6.9 (69) (racemic) 4-27 Isomer 1 5.0 (65) NT NT 6.6 (59) 4-27 Isomer 2 7.0 (120) <4.7 (13) <4.7 (4) 8.0 (104) 4-30 Isomer 1 5.9 (49) NT NT 6.8 (63) 4-31 Isomer 2 6.1 (66) <4.7 (4) <4.7 (4) 7.5 (88) 4-34 Isomer 2 5.7 (34) <4.7 (2) <4.7 (1) 7.0 (83) 4-35 Isomer 2 6.0 (57) NT NT 7.5 (108) 4-36 Isomer 2 4.9 (35) <4.7 (52) <4.7 (1) 7.1 (106) 4-37 Isomer 1 6.4 (84) <4.7 (3) <4.7 (7) 8.3 (138) 4-37 Isomer 2 6.1 (29) NT NT <4.7 (13) 4-38 Isomer 1 6.0 (72) <4.7 (7) <4.7 (3) 7.2 (97) 4-38 Isomer 2 <4.7 (25) <4.7 (3) <4.7 (1) 7.5 (95) 4-39 Isomer 2 6.1 (56) <4.7 (87) <4.7 (8) 7.2 (88) 4-40 Isomer 2 5.1 (37) <4.7 (4) <4.7 (6) 7.4 (109) 4-41 Isomer 2 <4.7 (8) <4.7 (5) <4.7 (42) 7.0 (86) 4-42 Isomer 2 <4.7 (16) NT NT 6.7 (52) 4-43 Isomer 2 <4.7 (6) <4.7 (5) <4.7 (6) 7.1 (75) 4-44 Isomer 3 6.7 (40) <4.7 (7) <4.7 (3) 7.3 (43) 4-44 Isomer 4 5.9 (67) <4.7 (14) <4.7 (10) 7.1 (97) 4-45 Isomer 2 6.0 (59) NT NT 6.5 (36) 4-46 Isomer 3 6.9 (90) <4.7 (3) <4.7 (3) 7.6 (76) 4-47 mixture 6.0 (86) <4.7 (7) <4.7 (7) 7.2 (106) of diastereomers 4-48 mixture 6.3 (56) <4.7 (3) <4.7 (11) 7.0 (77) of diastereomers 5-1 Isomer 1 5.6 (113) NT NT 5.5 (68) 5-2 Isomer 2 6.9 (92) <4.7 (143) <4.7 (5) 6.5 (50) 6-1 Isomer 2 6.2 (77) <4.7 (13) <4.7 (11) 6.9 (68) 6-2 Isomer 2 7.2 (109) <4.7 (0) <4.7 (10) 7.7 (114) 6-4 Isomer 2 7.5 (89) <4.7 (20) <4.7 (26) 8.4 (100) 6-5 Isomer 2 5.7 (56) NT NT <4.7 (20) 6-6 Isomer 1 6.3 (36) NT NT <4.7 (10) 6-6 Isomer 2 6.8 (71) <4.7 (3) <4.7 (4) 6.5 26) 6-8 Isomer 2 5.5 (55) <4.7 (10) <4.7 (100) 7.2 (103) 6-9 Isomer 2 <4.7 (17) <4.7 (1) <4.7 (50) 7.4 (84) 6-10 Isomer 2 5.9 (90) NT NT 7.4 (109) 6-11 Isomer 2 6.2 (86) NT NT 7.4 (111) 6-12 Isomer 1 <4.7 (6) NT NT 6.1 (51) 7-1 racemic 8.3 (26) <4.7 (0) <4.7 (4) <4.7 (14) 8-1 mixture of 8.0 (70) <4.7 (0) <4.7 (2) 8.7 (70) diastereomers 8-2 mixture of 6.7 (65) <4.7 (1) <4.7 (1) 8.0 (30) diastereomers 8-3 Isomer 2 <4.7 (12) <4.7 (2) <4.7 (4) 8.5 (39) 8-4 racemic 6.7 (63) <4.7 (4) <4.7 (1) 8.1 (91) NT—not tested

Example B

Passive Avoidance

Studies were carried out as described previously by Foley et al., (2004) Neuropsychopharmacology. In the passive avoidance task scopolamine administration (1 mg/kg, i.p.) at 6 hours following training rendered animals amnesic of the paradigm. A dose range of 3, 10, and 30 mg/kg (po) free base, administered 90 minutes prior to the training period via oral gavage, was examined.

Data for Examples 3-2 Isomer 2, 4-3 Isomer 2, 4-12 Isomer 3 and 4-27 Isomer 2 are shown in FIG. 1.

Example C

Effect of a Novel Test Compound and Xanomeline on d-Amphetamine-Induced Hyperactivity in Rats

The aim of the study is to examine the effect of a novel test compound on d-amphetamine induced hyperactivity in rats. Schizophrenia is a complex multifactorial disease that cannot be fully represented by a single experimental procedure. Antipsychotic-like behaviour was assessed in rats by the inhibition of hyperactivity (or hyperlocomotion) elicited by d-amphetamine. This procedure is sensitive to clinically relevant dopamine receptor antagonists and is therefore considered suitable for comparing muscarinic agonists that influence dopaminergic signalling. A dose of xanomeline previously observed to significantly reduce d-amphetamine induced hyperactivity was employed as a positive control. Statistical analysis typically involved three-way analysis of covariance or robust regression with treatment, day and rack as factors and activity during the 30 minutes prior to treatment as a covariate, followed by appropriate multiple comparison tests. A P value of <0.05 was considered statistically significant and is marked accordingly in all subsequent figures.

Data for Examples 4-12 Isomer 3 and 4-27 Isomer 2 are shown in FIG. 2.

Example D Pharmaceutical Formulations (i) Tablet Formulation

A tablet composition containing a compound of the formula (1), (1a) or (1b) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1), (1a) or (1b) with 100 mg lactose and optionally 1% by weight of magnesium stearate and filling the resulting mixture into standard opaque hard gelatin capsules.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application. 

1. The invention provides a compound of the formula (1):

or a salt thereof, wherein: p is 0, 1 or 2; q is 1 or 2; r is 1 or 2; s is 1 or 2, where the total of r and s is 2 or 3; X is C or N; Z is CH₂, N, O or S; Y is N, O, S or C; R¹ can be H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵, SO₂R⁵ or SO₃R⁵; R² can be independently H, halo, CN, OH, C_(1,3) alkoxy, NH₂, optionally substituted C_(1,6) alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, NR⁵R⁶, COOR⁵, CONR⁵R⁶, NR⁷CONR⁵R⁶, NR⁷COOR⁵, OCONR⁵R⁶, SR⁵, SOR⁵ or SO₂R⁵; or R¹ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R³ can be independently H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₃₋₆ cycloalkenyl, W or CH₂—W where W is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or R³ and R² together form an optionally substituted cycloalkyl or heterocycloalkyl ring; R⁴ can be H, optionally substituted C₁₋₅ alkyl, optionally substituted C₁₋₅ alkenyl, optionally substituted C₁₋₅ alkynyl, optionally substituted C₂₋₆ cycloalkyl or optionally substituted C₂₋₆ cycloalkenyl; and R⁵, R⁶ and R⁷ can be independently or C₁₋₆ alkyl.
 2. The compound according to claim 1 wherein R¹ is selected from H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₁₋₆ alkyl and CH₂—W where W is an optionally substituted 6 membered aryl or heteroaryl ring.
 3. The compound according to claim 1 wherein R¹ is selected from H, halo, CN, OH, C₁₋₃ alkoxy, NH₂, C₃₋₆ cycloalkyl and C₁₋₆ alkyl.
 4. The compound according to claim 1 wherein R² is selected from H, methyl, ethyl, propyl, isopropyl, cyclobutyl and benzyl, or R³ and R² together form a cycloalkyl ring.
 5. The compound according to claim 1 wherein R³ is H or C₁₋₅ alkyl.
 6. The compound according to claim 1 wherein R⁴ is selected from H, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.
 7. The compound according to claim 1 wherein p is
 0. 8. The compound according to claim 1 wherein q is
 1. 9. The compound according to claim 1 where Z is CH₂, N or O.
 10. The compound according to claim 1 wherein X is C.
 11. The compound according to claim 1 wherein r is 1 and s is
 1. 12. The compound according to claim 1 wherein r is 1 and s is
 2. 13. The compound according to claim 1 wherein r is 2 and s is
 1. 14. The compound according to claim 1 which is ethyl 6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(3-ethyl-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(3′-oxotetrahydro-1H-spiro[piperidine-4,1′-pyrrolo[1,2-c][1,3]oxazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, methyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-methyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3-oxo-1-propyl-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(1-benzyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-benzyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(6-fluoro-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, (²H₃)methyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, propan-2-yl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, 2-fluoroethyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, 8-(6-butanoyl-6-azaspiro[3.4]oct-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one, ethyl 2-(2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[2-oxo-3-(propan-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(2-methylpropyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(cyclopropylmethyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[2-oxo-4-(propan-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-cyclopropyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-cyclobutyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-[2-oxo-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[2-oxo-4-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-benzyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[2-oxo-4-(pyridin-2-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-ethyl-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-ethyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[4-ethyl-3-(2-methylpropyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(cyclopropylmethyl)-4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(12-oxo-11-oxa-8,13-diazadispiro[3.0.5.3]tridec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(12-oxo-11-oxa-8,13-diazadispiro[3.0.5.3]tridec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(2,2-difluoro-12-oxo-11-oxa-8,13-diazadispiro[3.0.5.3]tridec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(13-oxo-12-oxa-9,14-diazadispiro[4.0.5.3]tetradec-9-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3,4,4-trimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[4,4-dimethyl-3-(²H₃)methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(3-ethyl-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3-ethyl-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(4,4-dimethyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4,4-dimethyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[4,4-dimethyl-3-(2-methylpropyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(cyclopropylmethyl)-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(2-fluoroethyl)-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(2-methoxyethyl)-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(cyanomethyl)-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[4,4-dimethyl-2-oxo-3-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3′-oxotetrahydro-1H-spiro[piperidine-4,1′-pyrrolo[1,2-c][1,3]oxazol]-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(3′-oxotetrahydro-1H-spiro[piperidine-4,1′-pyrrolo[1,2-c][1,3]oxazol]-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[4-ethyl-3-(²H₃)methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3-cyclopropyl-4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(4-ethyl-3-methoxy-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(2-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(1-ethyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-ethyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-oxo-1-(propan-2-yl)-1,2,8-triazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-benzyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-ethyl-2-methyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1,2-diethyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(1-ethyl-3-oxo-2-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(2-methyl-3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[2-(²H₃)methyl-3-oxo-1-propyl-1,2,8-triazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[1-ethyl-2-(²H₃)methyl-3-oxo-1,2,8-triazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, ethyl 6-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, ethyl 6-(3,4-diethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, ethyl 6-(4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, or ethyl 6-(3-ethyl-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate.
 15. The compound according to claim 1 which is ethyl 6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, ethyl 6-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate, methyl 2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, methyl 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-(2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate, ethyl 2-[3-(cyclopropylmethyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl]-6-azaspiro[3.4]octane-6-carboxylate, ethyl 6-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate, or ethyl 6-(3-ethyl-4,4-dimethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azaspiro[3.4]octane-2-carboxylate.
 16. (canceled)
 17. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.
 18. The compound according to claim 1 which has muscarinic M₁ and/or M₄ receptor agonist activity.
 19. A method of treating a cognitive disorder or a psychotic disorder in a subject or treating or lessening the severity of acute, chronic, neuropathic, or inflammatory pain in a subject, comprising administering an effective amount of the compound according to claim 1 to the subject.
 20. A method of treating Alzheimer's Disease, dementia with Lewy bodies and other cognitive disorder in a subject, treating or lessening the severity of acute, chronic, neuropathic, or inflammatory pain in a subject, treating addiction in a subject, or treating movement disorders in a subject, comprising administering to the subject the compound according to claim 1 that exhibits selectivity for the M₁ receptor and/or the M₁ and M₄ receptor relative to the M₂ and M₃ receptor subtypes.
 21. A method of treating schizophrenia or other psychotic disorder in a subject, treating or lessening the severity of acute, chronic, neuropathic, or inflammatory pain in a subject, treating addiction in a subject, or treating movement disorders in a subject, comprising administering to the subject the compound according to claim 1 that exhibits selectivity for the M₄ receptor relative to the M₁, M₂ and M₃ receptor subtypes. 